Aminomethylene pyrazolones with therapeutic activity

ABSTRACT

A compound having the structure according to formula III 
     
       
         
         
             
             
         
       
     
     wherein:
         X is NH or S;   R 1  is H or (1C-4C)alkyl;   R 2  is (1C-4C)alkyl, phenyl or a monocyclic aromatic ring having one or more N—, O— or S— atoms in the ring, which alkyl, phenyl or aromatic ring is optionally substituted with one or more groups selected from (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, phenyloxy, phenylthio, halogen, or nitro;   R 3  and R 4  are each independently H, (1C-6C)alkyl, (2C-6C) alkenyl, (2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl, phenyl, a monocyclic aromatic ring having one or more N—, O— or S— atoms in the ring, a monocyclic non-aromatic ring having one or more N—, O— or S— atoms in the ring, each optionally substituted with hydroxyl, (1C-4C)alkoxy, phenyl, cycloalkyl, piperidyl, piperazinyl, furyl, thienyl, pirazinyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrrolidonyl, pyrrolinyl, imidazolinyl, imidazolyl, a monocyclic aromatic ring having one or more N—, O— or S— atoms in the ring, whereby each of these optional substituents is optionally further substituted with (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, halogen, nitro or (1C-2C)dioxol forming a ring; or   R 3  and R 4  form together pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl, pyrrolinylimidazolidinyl, imidazolinyl, piperidyl, piperazinylmorpholinyl, each optionally substituted with (1C-6C)alkyl, phenyl(1C-4C)alkyl, phenylketo(1C-4C)alkyl;   R 5  is H, Cl, F, Br, Me, NO 2 , t-butyl, OCF 3 , OCH 3 , CF 3 ;   R 6  is H, (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, nitro or halogen;   R 7  is H, F, Cl, Br, Me, NO 2 , t-butyl, OCF 3 , OCH 3 , CF 3 ; or pharmaceutically acceptable addition salts thereof for use in treatments of carcinoma, in particular, to delay, prevent or reverse metastasis in prostate cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/590,797, filed May 9, 2017, pending, which is a divisional of U.S.patent application Ser. No. 15/216,884, filed Jul. 22, 2016, now U.S.Pat. No. 9,676,764, issued Jun. 13, 2017, which is a divisional of U.S.patent application Ser. No. 14/383,083, filed Sep. 4, 2014, now U.S.Pat. No. 9,453,012, issued Sep. 27, 2016, which is a national phaseentry under 35 U.S.C. § 371 of International Patent ApplicationPCT/EP2013/054449, filed Mar. 5, 2013, designating the United States ofAmerica and published in English as International Patent Publication WO2013/131931 Al on Sep. 12, 2013, which claims the benefit under Article8 of the Patent Cooperation Treaty to European Patent Application SerialNo. 12183784.3, filed Sep. 10, 2012, and to European Patent ApplicationSerial No. 12158253.0, filed Mar. 6, 2012, the disclosure of each ofwhich is hereby incorporated herein in its entirety by this reference.

TECHNICAL FIELD

The invention is in the field of medicinal treatment of carcinoma, inparticular, by using a compound with a core structure of aminomethylenepyrazolone.

BACKGROUND

Carcinomas, which are cancers that originate from epithelial tissues,comprise the most dangerous types of cancers. Gastric, bladder andesophageal cancer are examples of carcinomas of epithelial origin.Glandular tissue often is of epithelial origin, so that breast cancer,prostate cancer and pancreas cancer also belong to the group of cancersfrom epithelial origin.

If a carcinoma is diagnosed early and still localized, the disease iscurable by surgery, radiation therapy with or without (neo)adjuvant andchances of survival are high (>90%). However, in early stages, cancerscan grow slowly and can remain locally confined for many years withoutcausing overt symptoms. Notorious in this respect is prostate cancer.Therefore, such types of cancer often remain undiagnosed until cancerouscells have already spread beyond the prostate into the surroundingtissues (local spread) or eventually migrate (metastasize) through theblood stream or lymphatic spread into other areas of the body.

Progressive growth of epithelial cancer and invasive metastasis involvesa multistep process. Tumors can generally not grow beyond a certainsize, due to a lack of oxygen and other essential nutrients. However,tumors induce blood vessel growth by secreting various growth factorsthat induce capillary growth into the tumor to supply nutrients,allowing for tumor expansion. This physiological process is calledangiogenesis. Angiogenesis is a normal and vital process in growth anddevelopment, such as in wound healing, but also a fundamental step inthe transition of tumors from small harmless clusters of cells to amalignant tumor. Angiogenesis is also required for the spread, ormetastasis, of a tumor. Single cancer cells can break away from anestablished solid tumor, enter the blood vessel, and be carried to adistant site, where they can implant and begin the growth of a secondarytumor. Such spread to other tissues (metastasis) involves invasion ofother parts of the body by mesenchymal cells. Cancer cell invasion andspread is determined by epithelial-mesenchymal-transition (EMT). Thespread to other tissues is preceded by transition of the epithelialcells to mesenchymal cells, indicated as epithelial-mesenchymaltransition (EMT). Thereby the incipient cancer cells acquiremesenchymal, fibroblast-like properties and show reduced intercellularadhesion and increased motility, endowing the incipient cancer cellswith invasive and metastatic properties. The reversed process in whichmesenchymal-to-epithelial transition (MET), creates new secondary tumorsat the other sites. Many patients die when diagnosed with an aggressiveform of cancer in which the cancerous cells have spread, ormetastasized.

It is important to improve the efficacy of medicinal treatment byproviding compounds that can interfere with the metastasis of cells,more in particular, compounds that can reverse EMT or interfere with theprocess of EMT.

Some treatment options of carcinomas are available, but are of limitedsuccess and provide no permanent cure. For prostate or breast cancerendocrine therapy, also called hormone deprivation therapy, has longbeen considered as the main suppression therapy to control neoplasms.The goal is to limit the body's production of the hormones. However,current endocrine therapy does not cure prostate or breast cancer.Moreover, it has become clear that expansive growth of cancer cells thatbecome unresponsive (resistant) to the current available endocrinetherapies is inevitable. In addition, it was found that in the majorityof advanced cancers the hormone receptor mediated signaling pathway isstill active, even at extremely low hormone levels. At this stage, thecancer can no longer be treated with available therapy and often resultsin progression to a lethal disease.

New chemotherapeutic drugs demonstrating improved response rates andprolonged survival are being developed. One of the examples is docetaxel(Taxotere). Unfortunately, chemotherapy reaches all parts of the body,not just only the cancer cells. It has been established that thesetherapies have serious side effects. Patients will undergo low bloodcell counts, nausea, vomiting, abdominal pain, diarrhea, hair loss,impotence, incontinence and other unwanted symptoms. Hence, the sideeffects significantly hamper the quality of life of the patients. Manyscientists are convinced that this treatment will offer little room forfuture improvements and has come close to the end of its product lifecycle. Docetaxel is the current standard of care for patients that areunresponsive to the currently available endocrine therapies. In view oflimited curative potential of docetaxel, and also in view of betterunderstanding of the underlying etiology of the disease and improvedearly diagnosis, there is an urgent need for novel treatment strategiesto prevent the progression, treat the tumor and avoid metastasis of thisdisease. In the present invention new compounds and a new use of suchcompounds for use in these novel treatment strategies are found within achemical group with a core structure of4-(aminomethylene)-2-(2-benzothiazolyl)-2,4-dihydro-3H-pyrazol-3-one or4-(aminomethylene)-2-(1H-benzimidazol-2-yl)-2,4-dihydro-3H-pyrazol-3-one.In Wu et al. (J. Med. Chem., vol. 55-2597-2605; 2012) a compound2-(2-benzothiazolyl)-4-[1-[[(3,4-dichlorphenyl)methyl]amino]ethylidene]-2,4-dihydro-5-(trifluoromethyl)-3H-pyrazol-3-oneis drawn in a table, whereby some weak activity in one of the usedbiochemical assays for inhibition of 5-lipoxygenase is displayed. Theactivity is not confirmed in a second assay, so a speculative link toany therapeutic activity cannot be justified from this information. Inpublished texts on suggested inhibitors of O-linked and N-linked glycanglycosylation two structures of compounds within this chemical group,namely2-(2-benzothiazolyl)-4-[1-[(2-ethoxyphenyl)amino]ethylidene]-2,4-dihydro-5-phenyl-3H-pyrazol-3-oneand2-(2-benzothiazolyl)-2,4-dihydro-4-[[[(4-methoxyphenyl])methyl]amino]methylene]-5-phenyl-3H-pyrazol-3-oneare drawn without indicating a method of synthesis. In this context thepossibility is discussed of therapeutic activity of such inhibitors, butsuch a target is not plausibly validated as model for any treatmenttarget. Compounds with the mentioned core structures seem also to havebeen passed in screening tests with targets for anti-infective effects(U.S. 2003/0229065), for: “Life span prolongation” (WO 2009/086303, U.S.2009/163545), for herbicide and fungicide activity (EP0274642), formuscular dystrophy (WO 2007/091106) and for anti-inflammatory effects byphosphodiesterase inhibition (PDE4) (WO 2008/045664). In WO 2005/094805the compound2-(2-benzothiazolyl)-4-[(dimethylamino)methylene]-2,4-dihydro-5-methyl-3H-pyrazol-3-oneis used as synthesis intermediate. In compounds in Reis et al. (Eur. J.Med. Chem. vol. 46, pp. 1448-1452, 2011) the aminomethylene pyrazolonestructure may be recognized in a fixed structure ofpyrazoloquinolinones. None of these disclosures reach out to the presentinvention.

BRIEF SUMMARY

The present invention provides for compounds having the structureaccording to formula I:

wherein:

-   -   X is NH or S;    -   R¹ is H or (1C-4C)alkyl;    -   R² is (1C-4C)alkyl, phenyl or a monocyclic aromatic ring having        one or more N—, O— or S— atoms in the ring, which alkyl, phenyl        or aromatic ring is optionally substituted with one or more        groups selected from (1C-4C)alkyl, (1C-4C)alkyloxy,        halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, phenyloxy, phenylthio,        halogen, or nitro;    -   R³ and R⁴ are each independently H, (1C-6C)alkyl, (2C-6C)        alkenyl, (2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl, phenyl, a        monocyclic aromatic ring having one or more N—, O— or S— atoms        in the ring, a monocyclic non-aromatic ring having one or more        N—, O— or S— atoms in the ring, each optionally substituted with        hydroxyl, (1C-4C)alkoxy, phenyl, cycloalkyl, piperidyl,        piperazinyl, furyl, thienyl, pirazinyl, pyrrolyl, 2H-pyrrolyl,        pyrazolyl, isoxazolyl, isothiazolyl, pyrrolidonyl, pyrrolinyl,        imidazolinyl, imidazolyl, a monocyclic aromatic ring having one        or more N—, O— or S— atoms in the ring, whereby each of these        optional substituents is optionally further substituted with        (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,        halo(1C-4C)alkyloxy, halogen, nitro or (1C-2C)dioxol forming a        ring; or    -   R³ and R⁴ form together pyrrolyl, imidazolyl, pyrazolyl,        pyrrolidinyl, pyrrolinylimidazolidinyl, imidazolinyl, piperidyl,        piperazinylmorpholinyl, each optionally substituted with        (1C-6C)alkyl, phenyl(1C-4C)alkyl, phenylketo(1C-4C)alkyl;    -   R⁵ is H or CF₃;    -   R⁶ is H, (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,        halo(1C-4C)alkyloxy, nitro or halogen;    -   and pharmaceutically acceptable addition salts thereof.

Such compounds may advantageously be used for therapy, i.e., theprevention or treatment of a disease. More in particular, they may beused in the prevention or treatment of a carcinoma. Even more inparticular, the compounds according to the invention may be used in thetreatment or prevention of metastasis of a carcinoma.

The term “carcinoma” is used herein to indicate a cancer of epithelialorigin, more in particular, a disease selected from the group consistingof gastric cancer, bladder cancer, esophageal cancer, breast cancer,prostate cancer or pancreas cancer. In particular, the use for thetreatment or prevention of metastasis of prostate cancer is preferred.

In a more specific embodiment, the invention is directed to a compoundhaving the structure and meanings of symbols according to formula I andwherein R³ and R⁴ are independently hydrogen, methyl, ethyl, or propylor a group as represented in the following list of structures:

Or R³ ad R⁴ form together an optionally substituted ring as representedin the following structures:

Other embodiments of the invention are compounds according to the abovedefined embodiments, but therein:

-   -   R¹ is H or (1C-4C)alkyl;    -   R² is (1C-4C)alkyl, phenyl or a monocyclic aromatic ring having        one or more N—, O— or S— atoms in the ring, which alkyl, phenyl        or aromatic ring is optionally substituted with one or more        groups selected from (1C-4C)alkyl, OCF₃ or halogen; and    -   R⁵ and R⁶ are hydrogen; or pharmaceutically acceptable addition        salts thereof.

Preferred embodiments of the invention are as those defined above butwherein the meaning of X is S.

Other preferred embodiments are those as defined above, wherein R¹ is Hor (1C-4C)alkyl and wherein R² is (1C-4C)alkyl or phenyl.

Other preferred embodiments are the embodiments as defined above whereinR³ and R⁴ are both methyl or wherein R³ is hydrogen and R⁴ is as definedin the respective embodiments above.

More specific embodiments are those as defined above, but wherein R⁶ is(1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl, halo(1C-4C)alkyloxy,nitro or halogen.

Another preferred embodiment of the invention is a compound according toformula II:

or a pharmaceutically acceptable addition salt thereof.

In another embodiment of the invention, the compound having thestructure according to formula I, wherein:

-   -   X is NH or S;    -   R¹ is H or (1C-4C)alkyl;    -   R² is —Z or —Y—Z, wherein Y is —CH₂— or —CH₂—CH₂—, and Z is        phenyl or a monocyclic aromatic ring having one or more N—, O—        or S— atoms in the ring, optionally substituted with one or more        groups selected from (1C-4C)alkyl, (1C-4C)alkyloxy,        halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, phenyloxy, phenylthio,        halogen, or nitro from (1C-4C)alkyl, (1C-4C)alkyloxy,        halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, phenyloxy, phenylthio,        halogen, or nitro    -   or Z is thien-2-yl, optionally substituted at position 3, 4 or 5        with halogen    -   or Z is N-methylpyrol-3-yl or benzo[b]thien-2-yl or        2-naphthalenyl;    -   R³ and R⁴ are each independently H, (1C-6C)alkyl, (2C-6C)        alkenyl, (2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl, phenyl, a        monocyclic aromatic ring having one or more N—, O— or S— atoms        in the ring, a monocyclic non-aromatic ring having one or more        N—, O— or S— atoms in the ring, each optionally substituted with        hydroxyl, (1C-4C)alkoxy, phenyl, cycloalkyl, piperidyl,        piperazinyl, furyl, thienyl, pirazinyl, pyrrolyl, 2H-pyrrolyl,        pyrazolyl, isoxazolyl, isothiazolyl, pyrrolidonyl, pyrrolinyl,        imidazolinyl, imidazolyl, a monocyclic aromatic ring having one        or more N—, O— or S— atoms in the ring, whereby each of these        optional substituents is optionally further substituted with        (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,        halo(1C-4C)alkyloxy, halogen, nitro or (1C-2C)dioxol forming a        ring;    -   or R³ and R⁴ form together pyrrolyl, imidazolyl, pyrazolyl,        pyrrolidinyl, pyrrolinylimidazolidinyl, imidazolinyl, piperidyl,        piperazinylmorpholinyl, each optionally substituted with        (1C-6C)alkyl, phenyl(1C-4C)alkyl, phenylketo(1C-4C)alkyl;    -   R⁵ is H or CF₃;    -   R⁶ is H, (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,        halo(1C-4C)alkyloxy, nitro or halogen;    -   or pharmaceutically acceptable addition salts thereof.

In a preferred embodiment, the compound having the structure accordingto formula I, whereby X is S; R¹ is H; R² is Z and Z is phenyl,optionally substituted at meta or para position, or at both positions,with one or two substituents selected from the list consisting of —NO₂,halogen, CF₃, (1C-4C)alkyl and methoxy; or Z is thien-2-yl, optionallysubstituted at position 3, 4 or 5 with halogen; or Z isN-methylpyrol-3-yl or benzo[b]thien-2-yl or 2-naphthalenyl; R³, R⁴ areH, H or H, CH₃ or CH₃, H₃; R⁵ is H; and R⁶ is H, halogen or methoxy.

In another embodiment, the compound is defined as in the previousparagraph, but R² is phenyl, optionally substituted at meta or paraposition, or at both positions, with one or two substituents selectedfrom the list consisting of halogen, CF₃, (1C-4C)alkyl and methoxy or R²is thien-2-yl, optionally substituted at position 3, 4 or 5 with halogenor R² is N-methylpyrol-3-yl or benzo[b]thien-2-yl or 2-naphthalenyl.

In another embodiment of the invention, the compound having thestructure according to formula III:

wherein:

-   -   X is NH or S;    -   R¹ is H or (1C-4C)alkyl;    -   R² is —Z or —Y—Z, wherein Y is —CH₂— or —CH₂—CH₂—, and Z is        phenyl or a monocyclic aromatic ring having one or more N—, O—        or S— atoms in the ring, optionally substituted with one or more        groups selected from (1C-4C)alkyl, (1C-4C)alkyloxy,        halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, phenyloxy, phenylthio,        halogen, or nitro from (1C-4C)alkyl, (1C-4C)alkyloxy,        halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, phenyloxy, phenylthio,        halogen, or nitro;    -   or Z is thien-2-yl, optionally substituted at position 3, 4 or 5        with halogen;    -   or Z is N-methylpyrol-3-yl or benzo[b]thien-2-yl or        2-naphthalenyl;    -   R³ and R⁴ are each independently H, (1C-6C)alkyl, (2C-6C)        alkenyl, (2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl, phenyl, a        monocyclic aromatic ring having one or more N—, O— or S— atoms        in the ring, a monocyclic non-aromatic ring having one or more        N—, O— or S— atoms in the ring, each optionally substituted with        hydroxyl, (1C-4C)alkoxy, phenyl, cycloalkyl, piperidyl,        piperazinyl, furyl, thienyl, pirazinyl, pyrrolyl, 2H-pyrrolyl,        pyrazolyl, isoxazolyl, isothiazolyl, pyrrolidonyl, pyrrolinyl,        imidazolinyl, imidazolyl, a monocyclic aromatic ring having one        or more N—, O— or S— atoms in the ring, whereby each of these        optional substituents is optionally further substituted with        (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,        halo(1C-4C)alkyloxy, halogen, nitro or (1C-2C)dioxol forming a        ring;    -   or R³ and R⁴ form together pyrrolyl, imidazolyl, pyrazolyl,        pyrrolidinyl, pyrrolinylimidazolidinyl, imidazolinyl, piperidyl,        piperazinylmorpholinyl, each optionally substituted with        (1C-6C)alkyl, phenyl(1C-4C)alkyl, phenylketo(1C-4C)alkyl;    -   R⁵ is H, Cl, F, Br, Me, NO₂, t-butyl, OCF₃, OCH₃, CF₃;    -   R⁶ is H, (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,        halo(1C-4C)alkyloxy, nitro or halogen;    -   R⁷ is H, F, Cl, Br, Me, NO₂, t-butyl, OCF₃, OCH₃, CF₃,    -   or pharmaceutically acceptable addition salts thereof.

In a more specific embodiment, the compound having the structureaccording the formula III, whereby X is S; R¹ is H; R² is Z and Z isphenyl, optionally substituted at meta or para position, or at bothpositions, with one or two substituents selected from the listconsisting of —NO₂, halogen, CF₃, (1C-4C)alkyl and methoxy; or Z isthien-2-yl, optionally substituted at position 3, 4 or 5 with halogen;or Z is N-methylpyrol-3-yl or benzo[b]thien-2-yl or 2-naphthalenyl; R³,R⁴ are H, H or H, CH₃ or CH₃, CH₃; R⁵ is H; and R⁶ is H, halogen ormethoxy; R⁷ is H or Cl.

In all of the above described embodiments, excepting in those whereby R⁶is H, the compound has preferably R⁶ being methoxy.

Another, more specified embodiment of the invention is a compoundaccording to Formula III, wherein:

-   -   X is S;    -   R¹ is H, CH₃;

R² is CF₃, CH₃, phenylethyl,

wherein R^(a) is H, F, Cl, Br, I, NO₂, methyl, ethyl, isopropyl,t-butyl, methoxy or CF₃ and R^(b) is H, Cl or CH₃;

R³, R⁴ is H, H or H, CH₃, or CH₃, CH₃ or one of R³ or R⁴ is —CN orp-methoxyphenylmethyl or R³ and R⁴ together represent a ring

on the nitrogen of Formula III to represent a piperidyl or R³ and R⁴together represent a ring

on the nitrogen of Formula III to pyrrolidinyl, or R³ is methyl and R⁴is dichlorbenzyl

-   -   R⁵ is H, Cl, F, Br, Me, NO₂, t-butyl, OCF₃, OCH₃, CF₃,    -   R⁶ is H, F, Cl, Br, NO₂, CH₃, t-butyl, OCH₃, OCF₃, CF₃;    -   R⁷ is H, F, Cl, Br, Me, NO₂, t-butyl, OCF₃, OCH₃, CF₃.

A more preferred embodiment is a compound according to formula III,wherein:

-   -   X is S;    -   R¹ is H, CH₃;    -   R² is CF₃, CH₃, phenylethyl,

wherein R^(a) is H, F, Cl, Br, I, NO₂, methyl, ethyl, isopropyl,t-butyl, methoxy or CF₃ and R^(b) is H, Cl or CH₃;

-   -   R³, R⁴ is H, H or H, CH₃, or CH₃, CH₃ or one of R³ or R⁴ is —CN        or p-methoxyphenylmethyl or R³ and R⁴ together represent a ring

on the nitrogen of Formula III to represent a piperidyl or R³ and R⁴together represent a ring

on the nitrogen of Formula III to pyrrolidinyl, or R³ is methyl and R⁴is dichlorbenzyl

-   -   R⁵ is H, Cl;    -   R⁶ is H, F, Cl, NO₂, CH₃, t-butyl, OCH₃ or OCF₃;    -   R⁷ is H, Cl.

Another more preferred embodiment is a compound according to formulaIII, wherein:

-   -   X is S;    -   R¹ is H;    -   R² is CF₃, CH₃, phenylethyl,

wherein R^(a) is H, F, Cl, Br, I, NO₂, methyl, ethyl, isopropyl,t-butyl, methoxy or CF₃ and R^(b) is H, Cl or CH₃;

-   -   R³, R⁴ is H, H or H, CH₃, or together represent a ring

on the nitrogen of Formula III to represent piperidyl, or R³ is methyland R⁴ is dichlorbenzyl

-   -   R⁵ is H;    -   R⁶ is H, Cl, NO₂, CH₃, OCH₃, OCF₃;    -   R⁷ is H.

Another more specified preferred embodiment is a compound according toformula III, wherein:

-   -   X is S;    -   R¹ is H;    -   R² is CF₃, CH₃,

wherein R^(a) is H, F, Cl, Br, I, methyl, ethyl, isopropyl, t-butyl orCF₃ and R^(b) is H, Cl or CH₃;

-   -   R³, R⁴ is H, H or H, CH₃, or together represent a ring

on the nitrogen of Formula III to represent piperidyl, or R³ is methyland R⁴ is dichlorbenzyl

-   -   R⁵ is H;    -   R⁶ is H, Cl, NO₂, CH₃, OCH₃, OCF₃;    -   R⁷ is H.

In all embodiments the compounds defined comprise also theirpharmaceutically acceptable addition salts.

A further embodiment of the present invention is a compound according toformula III and defined as in the embodiments with formula III above butwherein R³ or R⁴ is not p-methoxyphenylmethyl.

A compound according to the invention is also a compound for use in atreatment of carcinoma, according to formula I, wherein:

-   -   X is NH or S;    -   R¹ is H or (1C-4C)alkyl;    -   R² is —Z or —Y—Z, wherein Y is —CH₂— or —CH₂—CH₂—, and Z is        phenyl or a monocyclic aromatic ring having one or more N—, O—        or S— atoms in the ring, optionally substituted with one or more        groups selected from (1C-4C)alkyl, (1C-4C)alkyloxy,        halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, phenyloxy, phenylthio,        halogen, or nitro from (1C-4C)alkyl, (1C-4C)alkyloxy,        halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, phenyloxy, phenylthio,        halogen, or nitro    -   or Z is thien-2-yl, optionally substituted at position 3, 4 or 5        with halogen    -   or Z is N-methylpyrol-3-yl or benzo[b]thien-2-yl or        2-naphthalenyl;    -   R³ and R⁴ are each independently H, (1C-6C)alkyl, (2C-6C)        alkenyl, (2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl, a monocyclic        aromatic ring having one or more N—, O— or S— atoms in the ring,        a monocyclic non-aromatic ring having one or more N—, O— or S—        atoms in the ring, each optionally substituted with hydroxyl,        (1C-4C)alkoxy, cycloalkyl, piperidyl, piperazinyl, furyl,        thienyl, pirazinyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl,        isoxazolyl, isothiazolyl, pyrrolidonyl, pyrrolinyl,        imidazolinyl, imidazolyl, a monocyclic aromatic ring having one        or more N—, O— or S— atoms in the ring, whereby each of these        optional substituents is optionally further substituted with        (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,        halo(1C-4C)alkyloxy, halogen, nitro or (1C-2C)dioxol forming a        ring;    -   or R³ and R⁴ form together pyrrolyl, imidazolyl, pyrazolyl,        pyrrolidinyl, pyrrolinylimidazolidinyl, imidazolinyl, piperidyl,        piperazinylmorpholinyl, each optionally substituted with        (1C-6C)alkyl, phenyl(1C-4C)alkyl, phenylketo(1C-4C)alkyl;    -   R⁵ is H or CF₃;    -   R⁶ is H, (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,        halo(1C-4C)alkyloxy, nitro or halogen;    -   or pharmaceutically acceptable addition salts thereof.

Another embodiment of the invention is a compound according to formulaI, wherein:

-   -   X is NH or S;    -   R¹ is H or (1C-4C)alkyl;    -   R² is a monocyclic aromatic ring having one or more N—, O— or S—        atoms in the ring, which aromatic ring is optionally substituted        with one or more groups selected from (1C-4C)alkyl,        (1C-4C)alkyloxy, halo(1C-4C)alkyl, halo(1C-4C)alkyloxy,        phenyloxy, phenylthio, halogen, or nitro;    -   R³ and R⁴ are each independently H, (1C-6C)alkyl, (2C-6C)        alkenyl, (2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl, a monocyclic        non-aromatic ring having one or more N—, O— or S— atoms in the        ring, each optionally substituted with hydroxyl, (1C-4C)alkoxy,        cycloalkyl, piperidyl, piperazinyl, furyl, thienyl, pyrrolyl,        2H-pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrrolidonyl,        pyrrolinyl, imidazolinyl, imidazolyl, whereby each of these        optional substituents is optionally further substituted with        (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,        halo(1C-4C)alkyloxy, halogen, nitro or (1C-2C)dioxol forming a        ring; or    -   R³ and R⁴ form together pyrrolyl, imidazolyl, pyrazolyl,        pyrrolidinyl, pyrrolinylimidazolidinyl, imidazolinyl, piperidyl,        piperazinylmorpholinyl, each optionally substituted with        (1C-6C)alkyl, phenyl(1C-4C)alkyl, phenylketo(1C-4C)alkyl;    -   R⁵ is H or CF₃;    -   R⁶ is H, (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,        halo(1C-4C)alkyloxy, nitro or halogen;    -   and pharmaceutically acceptable addition salts thereof.

A more specific embodiment of the invention is a compound according toformula III, wherein:

-   -   X is S;    -   R¹ is H, CH₃;    -   R² is phenylethyl,

wherein R^(a) is F, Cl, Br, I, NO₂, methyl, ethyl, isopropyl, t-butyl,methoxy or CF₃ and R^(b) is H, Cl or CH₃;

-   -   R³, R⁴ is H, H or H, CH₃, or CH₃, CH₃ or one of R³ or R⁴ is —CN        or p-methoxyphenylmethyl or R³ and R⁴ together represent a ring

on the nitrogen of Formula III to represent a piperidyl or R³ and R⁴together represent a ring

on the nitrogen of Formula III to pyrrolidinyl, or R³ is methyl and R⁴is dichlorbenzyl

-   -   R⁵ is H, Cl, F, Br, Me, NO₂, t-butyl, OCF₃, OCH₃, CF₃; preferred        is R⁵ is H, Cl;    -   R⁶ is H, F, Cl, Br, NO₂, CH₃, t-butyl, OCH₃, OCF₃, CF₃;    -   R⁷ is H, F, Cl, Br, Me, NO₂, t-butyl, OCF₃, OCH₃, CF₃; preferred        is R⁷ is H or Cl.

Most preferred is a compound according to formula III, wherein:

-   -   X is S;    -   R¹ is H;    -   R² is

wherein R^(a) is F, Cl, Br, I, methyl, ethyl, isopropyl, t-butyl or CF₃and R^(b) is H, Cl or CH₃;

-   -   R³, R⁴ is H, H or H, CH₃, or together represent a ring

on the nitrogen of Formula III to represent piperidyl, or R³ is methyland R⁴ is dichlorbenzyl

-   -   R⁵ is H;    -   R⁶ is H, Cl, NO₂, CH₃, OCH₃, OCF₃;    -   R⁷ is H.

When embodiments are defined as characteristics of a compound thisinvention also provides for the use of the compounds in therapy, morespecifically carcinoma, as are gastric cancer, bladder cancer,esophageal cancer, breast cancer, prostate cancer or pancreas cancerand, in particular, for patients wherein metastasis of the carcinoma, inparticular, prostate cancer, is diagnosed.

DETAILED DESCRIPTION

The terms used in the description have the following meaning:

The prefix (1C-4C) refers to the number of 1-4 carbon atoms in thealkyl, alkenyl or alkynyl group. The definition includes amongst othersa methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, vinyl,ethynyl, cyclopropyl and propynyl.

Halo or halogen means fluorine, chlorine, bromine, iodine.

Haloalkyl, haloalkenyl or haloalkynyl means respectively an alkyl,alkenyl and alkynyl substituted with one or more halogens.

A pharmaceutically acceptable addition salt is known in the art ofpharmaceutics, such as a chloride, maleate, lactate, etc.

It should be realized that the compounds according to the inventionexist in tautomeric isomers when R³ and/or R⁴ are hydrogen. As shown inthe formulas A, B and C below the double bond system over theaminomethylenepyrazolone [A] can shift to the iminomethylpyrazolonesystem in [B] so that the delocalized representation as in formula [C]would be an equivalent manner to represent the compounds according tothe invention. Anyway, these tautomeric isomers are comprised into thedefinition of the compounds according to the invention as defined withthe support of the formulas.

Furthermore, the double bond at the methylene, or methylidene if R¹ hasan alkyl meaning, and the imino bond can be in Z or E configuration. Thecompound according to the invention is not specified regarding thisisomerism. Only the outcome of the syntheses of specified compounds hasdetermined and thereby implicitly defines such characteristic ofparticular compounds.

A compound according to the invention may be prepared, for example, bystarting with preparation a 2,4-dihydropyrazol-3-one scaffold, which issynthesized through a condensation-cyclization reaction of suitablehydrazines and acetoacetate esters in either ethanol or ethanol/aceticacid mixtures at reflux temperatures where X=S and in methanolcontaining a catalytic amount of concentrated HCl where X=N. Thecyclization product is usually collected by filtration, rinsing of thefilter cake with ethanol and in vacuo drying.

In the second reaction step, the thus obtained 1,2-dihydropyrazol-3-oneis subjected to an aminomethylenation reaction in THF at roomtemperature. The precipitated product may be purified by filtration,rinsing of the filter cake with a suitable solvent and in vacuo drying.

In the third and final step, the aminomethylidenepyrazol-3-one istreated with a suitable primary amine in methanol or ethanol at roomtemperature or at any temperature leading up to reflux temperature ofthe reaction solvent. The product may be purified by filtration andrinsing with methanol or ethanol and in vacuo drying.

A pharmaceutically acceptable addition salt of a compound may beprepared according to conventional methods. Salts are usually obtainedby combining the free base with inorganic or organic acids such ashydrochloric, fumaric, maleic, citric or succinic acid.

The therapeutic or preventive effect of a compound according to theinvention can be obtained by administration of the compound to a patient(human or animal, male or female) in need of treatment by administeringthe compound either topically, locally or systemically. Any enteral orparenteral route, such as transdermal, transmucosal, oral, rectal,intravenous, intramuscular or subcutaneous, can be selected as mostsuitable under the circumstances of the condition of the patient and thelocation of cancer cells. The administration will be greatly aided bythe manufacture of pharmaceutical compositions comprising a compoundaccording to the invention. A pharmaceutical formulation of a compoundaccording to the invention can be prepared according to methods known inthe art, varying from conventional pills, tablets and solutions to moresophisticated formulations for depot formulations or formulationsadapted for particular routes of administration. Resorption of thecompound according to the invention by the patient can be facilitated ordelayed by pharmaceutical additives.

In therapeutic use it is possible to select particular regimes ofadministration for continuous or multiple dosing per day, or fordetailed treatment regimes for a certain period of time, for example, aweek, a month or other continuous or intermittent periods. In the fieldof cancer therapy it is often needed or beneficial to use more than onemethod to combat the disease. A compound according to the invention issuitable for combination treatment with other treatments.

Dose selection depends on routes of administration and type andcondition of the treated patient. The effective dose per administrationor per day will usually be in the range of 0.001-1000 mg per patient,or, expressed in amount per kg patient, in particular, in considerationof small weight patients (for example, children or animals) between0.0001-100 mg/kg. The preferred range is 0.01-5 mg/kg or 1-350 mg for anaverage human patient.

Without wanting to be bound by theory in the use of the invention, itwas found that an important contribution to the therapeutic mechanism ofcompounds of the invention can reside in interference with the processof invasion into healthy tissue, as, for example, the interactionbetween prostate cancer cells and the bone micro-environment.

For determining the effectiveness of the compounds according to theinvention, a model assay based on the migration of cells in a migrationchamber was employed. This model is accepted in the art as providingrepresentative data on the ability of cells to metastasize.

It was found that a preferred compound according to the inventioninhibits tumor cell invasion more than 25%. Particularly preferredcompound also showed dose-dependent anti-invasion activity of over 40%.The compounds according to the invention are thus capable of interferingwith the acquisition of an invasive phenotype in human prostate cancerby inhibiting the EMT process. The more potent compounds for this effectare most preferred in view of the reduced dosage needed for use intherapy.

Results % inhibition of invasion in invasion assays If more values aregiven these are Compound results of repeated assays

52 49 45

35

93 45

91

91

  89%

89 82 78

88

87 76

86

  76%

  75%

73

70

67

  57%

57

56

Further embodiments are compounds shown in the following table:

Treatment of mice with4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-phenyl-2,4-dihydro-pyrazol-3-onedecreased the number of bone lesions and metastatic tumor burden. Cancercells and tumor burden were monitored by whole body bioluminescenceimaging. The data show that a compound according to the inventionaffects the formation of de novo skeletal metastases byPC-3M-Pro4luc+cells in vivo. Such in vivo testing may lead to furtherselection, preference, deselection or disfavor of individual compoundsfor further programs for development of a compound for use in aprescription medicine. A particular compound of interest for suchadvanced testing is,4-(aminomethylene)-2-(2-benzothiazolyl)-2,4-dihydro-5-(3-chlorophenyl)-3H-pyrazol-3-one.

EXAMPLES Example 1 Preparation of4-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(2-methoxyphenyl)-2,4-dihydropyrazol-3-one

A solution of 1.00 g (4.45 mmol) of ethyl (2-methoxybenzoyl)acetate and743 mg (4.45 mmol) of 2-hydrazinobenzothiazole in 15 ml of ethanol,containing a few drops of AcOH, was refluxed overnight under a nitrogenatmosphere. After evaporating the reaction solvent and replacing it withdiethyl ether containing a small amount of acetone, the precipitate wasfiltered, washed with diethyl ether and dried to give 1.33 g (4.11 mmol,92%) of2-benzothiazol-2-yl-5-(2-methoxyphenyl)-1,2-dihydropyrazol-3-one. 1H-NMR(DMSO-d6): δ 12.40 (bs, 1H), 8.05 (d, 1H), 7.90 (d, 1H), 7.80 (s, 1H),7.50 (m, 2H), 7.40 (t, 1H), 7.20 (d, 1H), 7.10 (m, 1H), 6.05 (s, 1H),3.90 (s, 3H).

To a solution of 722 mg (2.23 mmol) of2-benzothiazol-2-yl-5-(2-methoxyphenyl)-1,2-dihydropyrazol-3-one in 15ml of THF was added N,N-dimethylformamide dimethylacetal (326 μl, 2.46mmol). The reaction was stirred overnight at room temperature under anitrogen atmosphere, after which, the reaction mixture was diluted witha small amount of diethyl ether. The solids were filtered off, washedwith diethyl ether and dried to give 824 mg (2.18 mmol, 98%) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-(2-methoxy-phenyl)-2,4-dihydropyrazol-3-one.1H-NMR (DMSO-d6): δ 8.00 (d, 1H), 7.75 (d, 1H), 7.50 (t, 1H), 7.40 (m,2H), 7.30 (m, 2H), 7.20 (d, 1H), 7.10 (t, 1H), 3.80 (s, 3H), 3.70 (s,3H), 3.35 (s, 3H).

A suspension of 625 mg (1.65 mmol) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-(2-methoxy-phenyl)-2,4-dihydropyrazol-3-onein 10 ml ethanol and 10 ml of a 25% ammonia solution was heated to 60°C. under a nitrogen atmosphere overnight. After cooling to roomtemperature, the reaction mixture was diluted with a little water, thesolids were filtered, washed with ethanol and dried to give 481 mg (1.37mmol, 83%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(2-methoxyphenyl)-2,4-dihydropyrazol-3-one.1H-NMR (DMSO-d6): δ 9.40 (bs, 2H), 8.00 (d, 1H), 7.80 (d, 1H), 7.70 (s,1H), 7.45 (m, 3H), 7.30 (t, 1H), 7.20 (d, 1H), 7.10 (t, 1H), 3.80 (s,3H).

Example 2 Preparation of4-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-phenyl-2,4-dihydro-pyrazol-3-one

A solution of 1.75 g (9.08 mmol) of ethyl benzoylacetate and 1.50 g(9.08 mmol) of 2-hydrazinobenzothiazole in 30 ml of ethanol was refluxedfor 4 hours under a nitrogen atmosphere. After cooling to roomtemperature, the precipitate was filtered, washed with cold ethanol,diethylether and dried to give 1.66 g (5.66 mmol, 62%) of2-benzothiazol-2-yl-5-phenyl-1,2-dihydropyrazol-3-one as a white solid.¹H-NMR (DMSO-d6): δ 12.90 (bs, 1H), 8.05 (d, 1H), 7.90 (m, 3H), 7.50 (m,4H), 7.30 (t, 1H), 6.10 (s, 1H).

To a solution of 190 mg (0.648 mmol) of2-benzothiazol-2-yl-5-phenyl-1,2-dihydropyrazol-3-one in 10 ml of THFwas added N,N-dimethylformamide dimethylacetal (90 μl, 0.680 mmol). Thereaction was stirred for 3 hours at room temperature under a nitrogenatmosphere, the solids were filtered off, washed with acetone and driedto give 125 mg (0.359 mmol, 55%) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydropyrazol-3-oneas a yellow solid. ¹H-NMR (DMSO-d6): δ 8.00 (d, 1H), 7.80 (d, 1H), 7.70(s, 1H), 7.65 (m, 2H), 7.55 (m, 3H), 7.40 (t, 1H), 7.30 (t, 1H), 3.75(s, 3H), 3.40 (s, 3H).

A suspension of 100 mg (0.287 mmol) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydropyrazol-3-onein 5 ml of a 25% ammonia solution was heated to 120° C. in a pressurevessel overnight. After cooling to room temperature, the solids werefiltered, washed with water and dried to give 48 mg (0.150 mmol, 52%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-phenyl-2,4-dihydro-pyrazol-3-oneas a yellow solid. ¹H-NMR (DMSO-d6): δ 9.05 (bs, 2H), 8.00 (m, 2H), 7.85(d, 1H), 7.75 (m, 2H), 7.55 (m, 3H), 7.45 (t, 1H), 7.30 (t, 1H).

Example 3 Preparation of4-[1-Aminomethylidene]-2-(1H-benzoimidazol-2-yl)-5-phenyl-2,4-dihydropyrazol-3-one

A solution of 500 mg (3.37 mmol) of 2-hydrazino-1H-benzimidazole and 713mg (3.70 mmol) of ethyl benzoylacetate of in 15 ml of methanolcontaining a catalytic amount of concentrated HCl. The reaction mixturewas stirred at 65° C. under a nitrogen atmosphere overnight. Aftercooling to room temperature, the precipitate was filtered and dried togive 966 mg (3.09 mmol, 92%) of2-(1H-benzoimidazol-2-yl)-5-phenyl-1,2-dihydropyrazol-3-one as thehydrochloride salt. 1H-NMR (DMSO-d6): δ 7.95 (m, 2H), 7.65 (m, 2H), 7.45(m, 3H), 7.20 (m 2H), 6.10 (s, 1H).

To a suspension of 100 mg (0.36 mmol) of2-(1H-benzoimidazol-2-yl)-5-phenyl-1,2-dihydropyrazol-3-onehydrochloride salt in 5 ml of dioxane was added N,N-dimethylformamidedimethylacetal (52 μl, 0.39 mmol). The reaction was stirred for 2 hoursat room temperature under a nitrogen atmosphere, after which, thereaction mixture was cooled on an ice bath and diluted with a smallamount of diethyl ether. The solids were filtered off, washed withdiethyl ether and dried to give 99 mg (0.30 mmol, 83%) of2-(1H-benzoimidazol-2-yl)-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydropyrazol-3-oneas a yellow solid. 1H-NMR (DMSO-d6): δ 13.40 (bs, 1H), 8.55 (bs, 2H),7.70 (s, 1H), 7.65 (m, 2H), 7.55 (m, 3H), 7.20 (m, 2H), 3.70 (s, 3H),3.40 (s, 3H).

A suspension of 50 mg (0.15 mmol) of2-(1H-benzoimidazol-2-yl)-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydropyrazol-3-onein 3 ml of a 25% ammonia solution was heated to 65° C. under a nitrogenatmosphere for 3 hours. After cooling to room temperature, the solidswere filtered and dried to give 32 mg (0.11 mmol, 70%) of4-[1-aminomethylidene]-2-(1H-benzoimidazol-2-yl)-5-phenyl-2,4-dihydropyrazol-3-oneas a yellow solid. 1H-NMR (DMSO-d6): δ 12.20 (bs, 1H), 9.40 (bs, 2H),8.05 (m, 1H), 7.70 (m, 2H), 7.50 (m, 5H), 7.10 (m, 2H).

Example 4 Preparation of4-[1-Aminomethylidene]-2-(4-chlorobenzothiazol-2-yl)-5-phenyl-2,4-dihydropyrazol-3-one

4-Chlorobenzothiazol-2-ylamine (5.04 g, 27.29 mmol) was suspended in 35ml of ethylene glycol at room temperature under a nitrogen atmosphere.Hydrazine hydrate (3.98 ml, 81.87 mmol) was added followed byconcentrated hydrochloric acid (2.24 ml, 27.29 mmol) and the resultingreaction mixture was heated on an oil bath to 150° C. After 1.5 hours, aprecipitate was formed and heating was continued for an additional 1.5hours, after which time, the mixture was cooled, water was added and theresulting solids were filtered, washed with water and dried to give 5.33g (26.69 mmol, 98%) of (4-chlorobenzothiazol-2-yl)-hydrazine. ¹H-NMR(DMSO-d6): δ 9.40 (bs, 1H), 7.62 (d, 1H), 7.25 (d, 1H), 6.95 (t, 1H),5.15 (bs, 2H).

A solution of 1.09 g (5.46 mmol) of(4-chlorobenzothiazol-2-yl)-hydrazine and 1.15 g (6.01 mmol) of ethylbenzoylacetate in 30 ml of ethanol was refluxed for 2 days under anitrogen atmosphere. The reaction mixture was cooled and the precipitatewas collected by filtration, washed with a little EtOH and dried to give1.56 g (4.76 mmol, 87%) of2-(4-chlorobenzothiazol-2-yl)-5-phenyl-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 12.80 (bs, 1H), 8.05 (d, 1H), 7.85 (m, 2H), 7.60-7.40 (m,4H), 7.35 (t, 1H), 6.15 (s, 1H).

To a solution of 657 mg (2.00 mmol) of2-(4-chlorobenzothiazol-2-yl)-5-phenyl-1,2-dihydro-pyrazol-3-one in 20ml of THF was added N,N-dimethylformamide dimethylacetal (293 μl, 2.26mmol). The reaction was stirred overnight at room temperature under anitrogen atmosphere, after which, the solids were filtered off, washedwith diethyl ether and dried to give 681 mg (1.78 mmol, 89%) of2-(4-chlorobenzothiazol-2-yl)-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 7.95 (d, 1H), 7.60 (m, 3H), 7.55 (m, 4H), 7.25 (t,1H), 3.75 (s, 3H), 3.40 (s, 3H).

A suspension of 545 mg (1.42 mmol) of2-(4-chlorobenzothiazol-2-yl)-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydro-pyrazol-3-onein 10 ml 7N ammonia solution in MeOH was heated to 100° C. in a pressurevessel for 18 hours. After cooling to room temperature, the solids werefiltered, washed with a little EtOH and dried to give 460 mg (1.37 mmol,91%) of4-[1-aminomethylidene]-2-(4-chlorobenzothiazol-2-yl)-5-phenyl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.45 (bs, 2H), 8.00 (m, 2H), 7.75 (m, 2H), 7.50 (m,4H), 7.35 (t, 1H).

Example 5 Preparation of4-[1-Aminomethylidene]-2-(5-chlorobenzothiazol-2-yl)-5-phenyl-2,4-dihydropyrazol-3-one

5-Chlorobenzothiazole-2-thiol (5.21 g, 25.83 mmol) was dissolved in 50ml DMF at room temperature under a nitrogen atmosphere. To the reactionmixture were added 4.28 g (31.00 mmol) of potassium carbonate and 1.93ml (31.00 mmol) of methyl iodide and stirring was continued overnight,after which time, TLC (silica, 25% EtOAc in PE 40/60) indicated completeconsumption of the starting material. Water was added to the reactionmixture and the resulting solids were filtered off, washed with waterand dried to give 5.35 g (24.80 mmol, 96%) of5-chloro-2-methylsulfanylbenzothiazole. ¹H-NMR (DMSO-d6): δ 8.05 (d,1H), 7.90 (s, 1H), 7.40 (d, 1H), 2.75 (s, 3H).

A mixture of 5-chloro-2-methylsulfanylbenzothiazole (5.03 g, 23.32 mmol)and hydrazine hydrate (11.33 ml, 233.17 mmol) in 5 ml of EtOH was heatedunder a nitrogen atmosphere to 100° C. After 3 hours, a heavyprecipitation was present in the reaction mixture, after which time, thesuspension was cooled, water was added and the resulting solids werecollected, washed with water and dried to give 4.43 g (22.83 mmol, 95%)of (5-chlorobenzothiazol-2-yl)-hydrazine. ¹H-NMR (DMSO-d6): δ 9.10 (bs,1H), 7.65 (d, 1H), 7.30 (s, 1H), 6.95 (d, 1H), 5.10 (bs, 2H).

A solution of 935 g (4.68 mmol) of (5-chlorobenzothiazol-2-yl)-hydrazineand 990 mg (5.15 mmol) of ethyl benzoylacetate in 30 ml of ethanol wasrefluxed overnight under a nitrogen atmosphere. The reaction mixture wascooled and the precipitate was collected by filtration, washed with alittle EtOH and dried to give 970 mg (2.96 mmol, 63%) of245-chlorobenzothiazol-2-yl)-5-phenyl-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 13.00 (bs, 1H), 8.05 (d, 1H), 7.90 (m, 3H), 7.50 (m, 3H),7.40 (t, 1H), 6.10 (s, 1H).

To a solution of 800 mg (2.44 mmol) of2-(5-chlorobenzothiazol-2-yl)-5-phenyl-1,2-dihydro-pyrazol-3-one in 20ml of THF was added N,N-dimethylformamide dimethylacetal (357 μl, 2.68mmol). The reaction was stirred overnight at room temperature under anitrogen atmosphere, after which, ether was added and the solids werefiltered off, washed with diethyl ether and dried to give 790 mg (2.06mmol, 85%) of245-chlorobenzothiazol-2-yl)-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.05 (d, 1H), 7.85 (s, 1H), 7.70 (s, 1H), 7.60-7.40(m, 5H), 7.35 (d, 1H), 3.75 (s, 3H), 3.40 (s, 3H).

A suspension of 650 mg (1.70 mmol) of2-(5-chlorobenzothiazol-2-yl)-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydropyrazol-3-onein 10 ml 7N ammonia solution in MeOH was heated to 100° C. in a pressurevessel for 24 hours. After cooling to room temperature, the solids werefiltered, washed with a little EtOH and dried to give 439 mg (1.38 mmol,82%) of4-[1-aminomethylidene]-2-(5-chlorobenzothiazol-2-yl)-5-phenyl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.50 (bs, 2H), 8.05 (m, 2H), 7.90 (s, 1H), 7.75 (m,2H), 7.50 (m, 3H), 7.40 (t, 1H).

Example 6 Preparation of4-[1-Aminomethylidene]-2-(6-chlorobenzothiazol-2-yl)-5-phenyl-2,4-dihydropyrazol-3-one

6-Chlorobenzothiazol-2-ylamine (5.44 g, 27.84 mmol) was suspended in 35ml of ethylene glycol at room temperature under a nitrogen atmosphere.Hydrazine hydrate (4.06 ml, 83.52 mmol) was added followed byconcentrated hydrochloric acid (2.28 ml, 27.84 mmol) and the resultingreaction mixture was heated on an oil bath to 150° C. After 3 hours themixture was cooled, poured onto water and the resulting solids werefiltered, washed with water and dried to give 4.98 g (24.94 mmol, 90%)of (6-chlorobenzothiazol-2-yl)-hydrazine. ¹H-NMR (DMSO-d6): δ 9.15 (bs,1H), 7.70 (s, 1H), 7.25 (d, 1H), 7.15 (d, 1H), 5.05 (bs, 2H).

A solution of 1.06 g (5.28 mmol) of(6-chlorobenzothiazol-2-yl)-hydrazine and 1.01 g (5.82 mmol) of ethylbenzoylacetate in 25 ml of ethanol was refluxed for 5 hours under anitrogen atmosphere. The reaction mixture was filtered while warm,washed with EtOH and dried to give 580 mg (4.76 mmol, 34%) of2-(6-chlorobenzothiazol-2-yl)-5-phenyl-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 13.00 (bs, 1H), 8.20 (s, 1H), 7.90 (m, 3H), 7.50 (m, 4H),6.10 (s, 1H).

To a solution of 580 mg (1.77 mmol) of2-(6-chlorobenzothiazol-2-yl)-5-phenyl-1,2-dihydropyrazol-3-one in 20 mlof THF was added N,N-dimethylformamide dimethylacetal (282 μl, 2.12mmol). The reaction was stirred for 3 hours at room temperature under anitrogen atmosphere, after which, the solids were filtered off, washedwith diethyl ether and dried to give 628 mg (1.78 mmol, 93%) of2-(6-chlorobenzothiazol-2-yl)-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.15 (s, 1H), 7.80 (d, 1H), 7.70 (s, 1H), 7.60 (m,2H), 7.50 (m, 3H), 7.45 (d, 1H), 3.70 (s, 3H), 3.40 (s, 3H).

A suspension of 420 mg (1.10 mmol) of2-(6-chlorobenzothiazol-2-yl)-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydro-pyrazol-3-onein 10 ml 7N ammonia solution in MeOH was heated to 100° C. in a pressurevessel for 24 hours. After cooling to room temperature, the solids werefiltered, washed with a little EtOH and dried to give 275 mg (0.775mmol, 70%) of4-[1-aminomethylidene]-2-(6-chlorobenzothiazol-2-yl)-5-phenyl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.50 (2bs, 2H), 8.20 (s, 1H), 8.00 (bs, 1H), 7.80(d, 1H), 7.70 (m, 2H), 7.50 (m, 4H).

Example 7 Preparation of4-[1-Aminomethylidene]-2-(6-methoxybenzothiazol-2-yl)-5-(3-trifluoromethylphenyl)-2,4-dihydropyrazol-3-one

6-Methoxybenzothiazol-2-ylamine (7.20 g, 40.00 mmol) was suspended in 40ml of ethylene glycol at room temperature under a nitrogen atmosphere.Hydrazine hydrate (5.80 ml, 120.00 mmol) was added followed byconcentrated hydrochloric acid (3.28 ml, 40.00 mmol) and the resultingreaction mixture was heated on an oil bath to 150° C. After 2.5 hoursthe mixture was cooled water was added and the resulting solids werefiltered, washed with water and dried to give 7.09 g (36.31 mmol, 91%)of (6-methoxybenzothiazol-2-yl)-hydrazine. ¹H-NMR (DMSO-d6): δ 8.75 (s,1H), 7.30 (s, 1H), 7.20 (d, 1H), 6.80 (d, 1H), 4.90 (bs, 2H), 3.70 (s,3H).

A solution of 789 mg (4.04 mmol) of(6-methoxybenzothiazol-2-yl)-hydrazine and 9.95 mg (4.04 mmol) of methyl(3-trifluorobenzoyl)acetate in 30 ml of ethanol was refluxed for 5 hoursunder a nitrogen atmosphere, cooled, the solids were filtered, washedwith EtOH and dried to give 1.06 g (2.71 mmol, 67%) of2-(6-methoxybenzothiazol-2-yl)-5-(3-trifluoromethylphenyl)-1,2-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 12.80 (bs, 1H), 8.20 (m, 2H), 7.80 (m, 2H), 7.70 (t,1H), 7.60 (s, 1H), 7.10 (d, 1H), 6.20 (s, 1H), 3.80 (s, 3H).

To a solution of 458 mg (1.17 mmol) of2-(6-methoxybenzothiazol-2-yl)-5-(3-trifluoromethylphenyl)-1,2-dihydro-pyrazol-3-onein 20 ml of THF was added N,N-dimethylformamide dimethylacetal (171 μl,1.29 mmol). The reaction was stirred for 2 hours at room temperatureunder a nitrogen atmosphere. Diethyl ether was added to induceprecipitation. After an additional hour of stirring, the reaction volumewas concentrated to ca 10% of the original volume, diethyl ether wasadded and the solids were filtered off, washed with diethyl ether anddried to give 450 mg (1.00 mmol, 86%) of2-(6-methoxybenzothiazol-2-yl)-4-[1-dimethylaminomethylidene]-5-(3-trifluoromethylphenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00-7.80 (m, 3H), 7.80-7.70 (m, 3H), 7.55 (s, 1H),7.05 (d, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.40 (s, 3H).

A suspension of 355 mg (0.725 mmol) of2-(6-methoxybenzothiazol-2-yl)-4-[1-dimethylaminomethylidene]-5-(3-trifluoromethylphenyl)-2,4-dihydropyrazol-3-onein 10 ml 7N ammonia solution in MeOH was heated to 100° C. in a pressurevessel overnight. After cooling to room temperature, the solids werefiltered, washed with a little EtOH and dried to give 280 mg (0.669mmol, 92%) of4-[1-aminomethylidene]-2-(6-methoxybenzothiazol-2-yl)-5-(3-trifluoromethylphenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.50 (2bs, 2H), 8.10 (m, 3H), 7.85 (d, 1H), 7.75 (m,2H), 7.60 (s, 1H), 7.05 (d, 1H), 3.80 (s, 3H).

Example 8 Preparation of4-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(3-trifluoromethylphenyl)-2,4-dihydro-pyrazol-3-one

A solution of 1.80 g (7.31 mmol) of benzothiazol-2-yl-hydrazine and 1.21g (7.31 mmol) of 3-(3-trifluoromethylphenyl)-3-oxo-propionic acid methylester in 50 ml of ethanol was refluxed for 5 hours under a nitrogenatmosphere, cooled, the solids were filtered, washed with EtOH and driedto give 2.12 g (5.87 mmol, 80%) of2-benzothiazol-2-yl-5-(3-trifluoromethylphenyl)-1,2-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 13.00 (bs, 1H), 8.20 (m, 2H), 8.05 (d, 1H), 7.90 (d,1H), 7.80 (s, 1H), 7.70 (m, 1H), 7.50 (t, 1H), 7.40 (t, 1H), 6.25 (s,1H).

To a solution of 414 mg (1.15 mmol) of2-benzothiazol-2-yl-5-(3-trifluoromethylphenyl)-1,2-dihydro-pyrazol-3-onein 10 ml of THF was added N,N-dimethylformamide dimethylacetal (160 ₁11,1.20 mmol). The reaction was stirred for 3 hours at room temperatureunder a nitrogen atmosphere. A small amount of diethyl ether was addedand the solids were filtered off, washed with diethyl ether and dried togive 398 mg (0.956 mmol, 83%) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-(3-trifluoromethylphenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00-7.70 (m, 7H), 7.50 (t, 1H), 7.45 (t, 1H), 3.70(s, 3H), 3.40 (s, 3H).

A suspension of 239 mg (0.574 mmol) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-(3-trifluoromethylphenyl)-2,4-dihydropyrazol-3-onein 10 ml 7N ammonia solution in MeOH was heated to 100° C. in a pressurevessel overnight. After cooling to room temperature, the solids werefiltered, washed with a little EtOH and dried to give 163 mg (0.420mmol, 73%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(3-trifluoromethylphenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.60 (bs, 2H), 8.10 (m, 4H), 7.90 (m, 2H), 7.80 (m,1H), 7.45 (t, 1H), 7.30 (t, 1H).

Example 9 Preparation of4-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(3-chlorophenyl)-2,4-dihydro-pyrazol-3-one

A solution of 1.00 g (4.20 mmol) of benzothiazol-2-yl-hydrazine and 730mg (4.20 mmol) of 3-(3-chlorophenyl)-3-oxopropionic acid ethyl ester in20 ml of ethanol was refluxed overnight under a nitrogen atmosphere,cooled, the solids were filtered, washed with EtOH and dried to give1.25 g (3.81 mmol, 91%) of2-benzothiazol-2-yl-5-(3-chlorophenyl)-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 13.00 (bs, 1H), 8.10 (d, 1H), 8.00-7.80 (m, 3H), 7.50 (m,3H), 7.40 (t, 1H), 6.20 (s, 1H).

To a solution of 647 mg (1.97 mmol) of2-benzothiazol-2-yl-5-(3-chlorophenyl)-1,2-dihydro-pyrazol-3-one in 15ml of THF was added N,N-dimethylformamide dimethylacetal (288 μl, 2.17mmol). The reaction was stirred for 2 days at room temperature under anitrogen atmosphere. The solids were filtered off, washed with diethylether and dried to give 706 mg (1.84 mmol, 94%) of2-benzothiazol-2-yl-5-(3-chlorophenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00 (d, 1H), 7.80 (d, 1H), 7.70 (2s, 2H), 7.60 (m,3H), 7.40 (t, 1H), 7.30 (t, 1H), 3.70 (s, 3H), 3.40 (s, 3H).

A suspension of 424 mg (1.11 mmol) of2-benzothiazol-2-yl-5-(3-chlorophenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-onein 5 ml EtOH and 20 ml of 25% aqueous ammonia solution was heated to 60°C. overnight. After cooling to room temperature, the solids werefiltered, washed with a little EtOH and dried to give 386 mg (1.09 mmol,98%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(3-chlorophenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.60 (bs, 2H), 8.10 (s, 1H), 8.00 (d, 1H), 7.90 (s,1H), 7.85 (d, 1H),7.65 (m, 2H), 7.45 (m, 2H), 7.30 (t, 1H).

Example 10 Preparation of4-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(3-methylphenyl)-2,4-dihydropyrazol-3-one

A solution of 801 mg (4.85 mmol) of benzothiazol-2-yl-hydrazine and 1.00g (4.20 mmol) of 3-(3-methylphenyl)-3-oxopropionic acid ethyl ester in25 ml of ethanol was refluxed for 22 hours under a nitrogen atmosphere,cooled, the solids were filtered, washed with a little cold EtOH anddried to give 1.41 g (4.59 mmol, 95%) of2-benzothiazol-2-yl-5-(3-methylphenyl)-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 12.90 (bs, 1H), 8.10 (d, 1H), 7.90 (d, 1H), 7.75 (s, 1H),7.70 (d, 1H), 7.50 (t, 1H), 7.40-7.20 (m, 4H), 6.10 (s, 1H), 2.40 (s,3H).

To a solution of 525 mg (1.71 mmol) of2-benzothiazol-2-yl-5-(3-methylphenyl)-1,2-dihydropyrazol-3-one in 10 mlof THF was added N,N-dimethylformamide dimethylacetal (238 μl, 1.79mmol). The reaction was stirred for 4 hours at room temperature under anitrogen atmosphere. The solids were filtered off, washed with diethylether and dried to give 565 mg (1.56 mmol, 91%) of2-benzothiazol-2-yl-5-(3-methylphenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00 (d, 1H), 7.80 (d, 1H), 7.70 (s, 1H), 7.50-7.20(m, 6H), 3.70 (s, 3H), 3.40 (s, 3H), 2.40 (s, 3H).

A suspension of 350 mg (0.966 mmol) of2-benzothiazol-2-yl-5-(3-methylphenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-onein 10 ml 7N ammonia solution in MeOH was heated to 100° C. in a pressurevessel overnight. After cooling to room temperature, the solids werefiltered, washed with a little EtOH and dried to give 300 mg (0.897mmol, 93%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(3-methylphenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.45 (bs, 2H), 8.00 (m, 2H), 7.80 (d, 1H), 7.60 (s,1H), 7.55 (d, 1H), 7.45-7.30 (m, 4H), 2.40 (s, 3H).

Example 11 Preparation of4-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(3-methoxyphenyl)-2,4-dihydro-pyrazol-3-one

A solution of 1.23 g (7.44 mmol) of benzothiazol-2-yl-hydrazine and 1.65g (7.44 mmol) of 3-(3-methoxyphenyl)-3-oxopropionic acid ethyl ester in40 ml of ethanol was refluxed for 5 hours under a nitrogen atmosphere,cooled, the solids were filtered, washed with EtOH and dried to give1.68 g (5.20 mmol, 70%) of2-benzothiazol-2-yl-5-(3-methoxyphenyl)-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 13.00 (bs, 1H), 8.10 (d, 1H), 7.90 (d, 1H), 7.55-7.30 (m,5H), 7.05 (m, 1H), 6.10 (s, 1H), 3.85 (s, 3H).

To a solution of 504 mg (1.56 mmol) of2-benzothiazol-2-yl-5-(3-methoxyphenyl)-1,2-dihydro-pyrazol-3-one in 10ml of THF was added N,N-dimethylformamide dimethylacetal (217 μl, 1.64mmol). The reaction was stirred overnight at room temperature under anitrogen atmosphere. The solids were filtered off, washed with acetoneand dried to give 549 mg (1.45 mmol, 93%) of2-benzothiazol-2-yl-5-(3-methoxyphenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00 (d, 1H), 7.80 (d, 1H), 7.70 (s, 1H), 7.45 (m,2H), 7.30 (t, 1H), 7.15 (m, 2H), 7.10 (d, 1H), 3.80 (s, 3H), 3.70 (s,3H), 3.40 (s, 3H).

A suspension of 266 mg (0.703 mmol) of2-benzothiazol-2-yl-5-(3-methoxyphenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-onein 10 ml 7N ammonia solution in MeOH was heated to 100° C. in a pressurevessel overnight. After cooling to room temperature, the solids werefiltered, washed with a little EtOH and dried to give 168 mg (0.479mmol, 68%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(3-methoxyphenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.40 (bs, 2H), 8.00 (m, 2H), 7.85 (d, 1H), 7.45 (m,2H), 7.40-7.20 (m, 3H), 7.10 (d, 1H), 3.80 (s, 3H).

Example 12 Preparation of4-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(3-bromo-4-methylphenyl)-2,4-dihydro-pyrazol-3-one

To a suspension of 376 mg NaH (9.39 mmol, 60% dispersion in mineral oil)in 30 ml of dry THF under a nitrogen atmosphere was slowly added diethylcarbonate (1.14 ml, 9.39 mmol) and 3-bromo-4-methylacetophenone (1.00 g,4.69 mmol). The reaction mixture was heated to 70° C. for 4 hours, afterwhich, TLC (silica, EtOAc/PE 40-60 2:3) indicated complete consumptionof the starting material. The mixture was cooled, 20 ml of water wasslowly added followed by 10 drops of AcOH and extraction with 2×200 mlof EtOAc. The combined organic layers were washed with 20 ml of water,20 ml of brine, dried over magnesium sulfate and evaporated to give 1.34g of 3-(3-bromo-4-methylphenyl)-3-oxopropionic acid ethyl ester, whichwas used without further purification. ¹H-NMR (CDCl3): δ 8.15 (s, 1H),7.80 (d, 1H), 7.40 (d, 1H), 4.20 (q, 2H), 3.90 (s, 2H), 2.50 (s, 3H),1.30 (t, 3H).

A solution of 776 mg (4.70 mmol) of benzothiazol-2-yl-hydrazine and 1.34g (4.70 mmol) of 3-(3-bromo-4-methylphenyl)-3-oxopropionic acid ethylester in 15 ml of ethanol was refluxed overnight under a nitrogenatmosphere, cooled, the solids were filtered, washed with a little coldEtOH and dried to give 1.80 g (4.66 mmol, 99%) of2-benzothiazol-2-yl-5-(3-bromo-4-methylphenyl)-1,2-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 12.90 (bs, 1H), 8.10 (s, 1H), 8.05 (d, 1H), 7.90 (d,1H), 7.80 (d, 1H), 7.50 (m, 2H), 7.40 (t, 1H), 6.15 (s, 1H), 2.40 (s,3H).

To a solution of 630 mg (1.63 mmol) of2-benzothiazol-2-yl-5-(3-bromo-4-methylphenyl)-1,2-dihydropyrazol-3-onein 10 ml of THF was added N,N-dimethylformamide dimethylacetal (240 μl,1.79 mmol). The reaction was stirred for 2 hours at room temperatureunder a nitrogen atmosphere. The solids were filtered off, washed withdiethyl ether and dried to give 610 mg (1.38 mmol, 85%) of2-benzothiazol-2-yl-5-(3-bromo-4-methylphenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00 (d, 1H), 7.80 (m, 2H), 7.70 (s, 1H), 7.50 (m,2H), 7.45 (t, 1H), 7.30 (t, 1H), 3.70 (s, 3H), 3.40 (s, 3H), 2.40 (s,3H).

A suspension of 250 mg (0.583 mmol) of2-benzothiazol-2-yl-5-(3-bromo-4-methylphenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-onein 5 ml EtOH and 5 ml of 25% aqueous ammonia solution was heated to 60°C. overnight. After cooling to room temperature, the solids werefiltered, washed with a little EtOH and dried to give 185 mg (0.448mmol, 77%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(3-bromo-4-methylphenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.50 (bs, 2H), 8.10 (s, 1H), 8.05 (d, 1H), 7.95 (s,1H), 7.85 (d, 1H),7.65 (d, 1H), 7.50 (m, 2H), 7.35 (t, 1H), 2.40 (s,3H).

Example 13 Preparation of4-[1-Aminomethylidene]-5-benzo[b]thiophen-2-yl-2-benzothiazol-2-yl-2,4-dihydropyrazol-3-one

To a suspension of 452 mg NaH (11.30 mmol, 60% dispersion in mineraloil) in 30 ml of dry THF under a nitrogen atmosphere was slowly addeddiethyl carbonate (1.38 ml, 11.30 mmol) and 2-acetylbenzo[b]thiophene(1.00 g, 5.67 mmol). The reaction mixture was heated to 70° C. for 3hours, cooled, 20 ml of water was slowly added followed by 10 drops ofAcOH and the mixture was extracted with 3×200 ml of EtOAc. The combinedorganic layers were washed with 20 ml of water, 100 ml of brine, driedover magnesium sulfate and evaporated to give 1.47 g of3-benzo[b]thiophen-2-yl-3-oxopropionic acid ethyl ester, which was usedwithout further purification. ¹H-NMR (DMSO-d6): δ 8.20 (s, 1H), 8.05(2d, 2H), 7.55 (t, 1H), 7.50 (t, 1H), 4.25 (s, 2H), 4.10 (q, 2H), 1.20(t, 3H).

A solution of 665 mg (4.03 mmol) of benzothiazol-2-yl-hydrazine and 1.0g (4.70 mmol) of 3-benzo[b]thiophen-2-yl-3-oxopropionic acid ethyl esterin 10 ml of ethanol and 2 ml of HOAc was refluxed overnight under anitrogen atmosphere, cooled, the solids were filtered, washed with alittle cold EtOH and dried to give 240 mg (0.689 mmol, 17%) of5-benzo[b]thiophen-2-yl-2-benzothiazol-2-yl-1,2-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 12.90 (bs, 1H), 8.10-7.80 (m, 5H), 7.55 (t, 1H),7.40 (m, 3H), 6.10 (s, 1H).

To a solution of 400 mg (1.15 mmol) of5-benzo[b]thiophen-2-yl-2-benzothiazol-2-yl-1,2-dihydropyrazol-3-one in10 ml of THF was added N,N-dimethylformamide dimethylacetal (170 μl,1.26 mmol). The reaction was stirred overnight at room temperature undera nitrogen atmosphere. The solids were filtered off, washed with THF anddried to give 286 mg (0.707 mmol, 61%) of5-benzo[b]thiophen-2-yl-2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.10 (s, 1H), 8.05 (m, 2H), 7.90 (m, 3H), 7.50 (m,3H), 7.35 (t, 1H), 3.75 (s, 3H), 3.55 (s, 3H).

A suspension of 100 mg (0.247 mmol) of5-benzo[b]thiophen-2-yl-2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-onein 4 ml EtOH and 4 ml of 25% aqueous ammonia solution was heated to 60°C. for 2 hours. After cooling to room temperature, the solids werefiltered, washed with a little EtOH and dried to give 55 mg (0.146 mmol,59%) of4-[1-aminomethylidene]-5-benzo[b]thiophen-2-yl-2-benzothiazol-2-yl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.70 (bs, 2H), 8.50 (s, 1H), 8.10 (s, 1H), 8.05 (m,2H), 7.90 (m, 2H), 7.50 (m, 3H), 7.35 (t, 1H).

Example 14 Preparation of4-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-thiophen-2-yl-2,4-dihydropyrazol-3-one

To a suspension of 630 mg NaH (15.85 mmol, 60% dispersion in mineraloil) in 40 ml of dry toluene under a nitrogen atmosphere was slowlyadded diethyl carbonate (1.92 ml, 15.85 mmol) and 2-acetylthiophene(1.00 g, 7.93 mmol). The reaction mixture was heated to 70° C. for 1hour, cooled, 200 ml of water was slowly added followed by 2 ml of AcOHand the mixture was extracted with 3×200 ml of EtOAc. The combinedorganic layers were washed with 100 ml of water, 300 ml of brine, driedover magnesium sulfate and evaporated to give a crude oil that waspurified by column chromatography (silica, 10% EtOAc in PE 40-60) togive 1.00 g (5.04 mmol, 64%) of 3-thiophen-2-yl-3-oxopropionic acidethyl ester. ¹H-NMR (CDCl3): δ 8.15 (s, 1H), 7.55 (m, 1H), 7.35 (m, 1H),4.20 (q, 2H), 3.90 (s, 2H), 1.25 (t, 3H).

A solution of 870 mg (5.25 mmol) of benzothiazol-2-yl-hydrazine and 1.04g (5.25 mmol) of 3-thiophen-2-yl-3-oxopropionic acid ethyl ester in 15ml of ethanol was refluxed for 18 hours under a nitrogen atmosphere,cooled, the solids were filtered, washed with a little cold EtOH anddried to give 1.38 g (4.61 mmol, 88%) of2-benzothiazol-2-yl-5-thiophen-2-yl-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 12.90 (bs, 1H), 8.05 (d, 1H), 7.90 (d, 1H), 7.65 (m, 2H),7.50 (t, 1H), 7.40 (t, 1H), 7.10 (s, 1H), 5.95 (s, 1H).

To a solution of 720 mg (2.41 mmol) of2-benzothiazol-2-yl-5-thiophen-2-yl-1,2-dihydropyrazol-3-one in 10 ml ofTHF was added N,N-dimethylformamide dimethylacetal (350 μl, 2.56 mmol).The reaction was stirred for 2 hours at room temperature under anitrogen atmosphere. Diethyl ether was added to induce precipitation,after which, the solids were filtered off, washed with diethyl ether anddried to give 753 mg (2.12 mmol, 88%) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-thiophen-2-yl-2,4-dihydropyrazol-3-oneas a mixture of isomers. In order to obtain one of the isomers pure, 5ml of DCM was added to the solid isomeric mixture, stirred thoroughlyand the liquid decanted from the remaining solids. The liquid wasconcentrated, the solids filtered and washed with 2 ml of DCM. Thecombined solids after two DCM washing cycles weighed 82 mg and consistedof one single isomer. ¹H-NMR (DMSO-d6): δ 8.00 (m, 2H), 7.85 (m, 1H),7.75 (s, 1H), 7.50 (s, 1H), 7.45 (m, 1H), 7.30 (m, 1H), 7.25 (s, 1H),3.75 (s, 3H), 3.50 (s, 3H).

A suspension of 500 mg (1.41 mmol) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-thiophen-2-yl-2,4-dihydropyrazol-3-onein 5 ml EtOH and 5 ml of 25% aqueous ammonia solution was heated to 60°C. for 1 hour. After cooling to room temperature, the solids werefiltered, washed with a little EtOH and dried to give 357 mg (1.09 mmol,78%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-thiophen-2-yl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.40 (bs, 2H), 8.30 (s, 1H), 8.05 (d, 1H), 7.90 (d,1H), 7.75 (d, 1H), 7.65 (m, 1H), 7.50 (t, 1H), 7.35 (t, 1H), 7.25 (m,1H).

Example 15 Preparation of4-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(5-bromothiophen-2-yl)-2,4-dihydropyrazol-3-one

To a suspension of 597 mg NaH (14.92 mmol, 60% dispersion in mineraloil) in 75 ml of dry THF under a nitrogen atmosphere was slowly addeddiethyl carbonate (1.81 ml, 14.92 mmol) and 2-acetyl-5-bromothiophene(1.53 g, 7.46 mmol). The reaction mixture was heated to 70° C. for 2hours, cooled, poured into iced water and acidified with AcOH. Themixture was extracted with EtOAc twice and the combined organic layerswere washed with water, brine, dried over magnesium sulfate andevaporated to give 1.82 g (6.57 mmol, 88%) of3-(5-bromothiophen-2-yl)-3-oxopropionic acid ethyl ester. ¹H-NMR(CDCl3): δ 7.5 (d, 1H), 7.30 (s, 1H), 7.15 (d, 1H), 4.20 (q, 2H), 3.85(s, 2H), 1.25 (t, 3H).

A solution of 1.08 g (6.57 mmol) of benzothiazol-2-yl-hydrazine and 1.82g (6.57 mmol) of 3-(5-bromothiophen-2-yl)-3-oxopropionic acid ethylester in 25 ml of ethanol containing 5 ml of AcOH was refluxed overnightunder a nitrogen atmosphere, cooled, the solids were filtered, washedwith a little cold EtOH and dried to give 1.58 g (4.18 mmol, 64%) of2-benzothiazol-2-yl-5-(5-bromothiophen-2-yl)-1,2-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 13.00 (bs, 1H), 8.05 (d, 1H), 7.90 (d, 1H), 7.50 (m,2H), 7.40 (t, 1H), 7.30 (s, 1H), 6.05 (s, 1H).

To a solution of 793 mg (2.10 mmol) of2-benzothiazol-2-yl-5-(5-bromothiophen-2-yl)-1,2-dihydropyrazol-3-one in15 ml of THF was added N,N-dimethylformamide dimethylacetal (292 μl,2.20 mmol). The reaction was stirred for 15 minutes at room temperatureunder a nitrogen atmosphere. The solids were filtered off, washed withTHF and dried to give 621 mg (1.43 mmol, 68%) of2-benzothiazol-2-yl-5-(5-bromothiophen-2-yl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00 (d, 1H), 7.95 (s, 1H), 7.85 (d, 1H), 7.45 (t,1H), 7.40-7.30 (m, 3H), 3.70 (s, 3H), 3.45 (s, 3H).

A suspension of 260 mg (0.60 mmol) of2-benzothiazol-2-yl-5-(5-bromothiophen-2-yl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-onein 10 ml 7N ammonia solution in MeOH was stirred at room temperature ina closed flask for 2 days followed by evaporation of the solvent to give241 mg (0.59 mmol, 99%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(5-bromothiophen-2-yl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.60 (bs, 2H), 8.30 (s, 1H), 8.05 (d, 1H), 7.90 (d,1H), 7.55 (m, 1H), 7.50 (t, 1H), 7.35 (m, 2H).

Example 164-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(3-bromophenyl)-2,4-dihydropyrazol-3-one

A solution of 609 mg (3.69 mmol) of benzothiazol-2-yl-hydrazine and 1.00g (3.69 mmol) of 3-(3-bromophenyl)-3-oxopropionic acid ethyl ester in 20ml of EtOH was refluxed overnight under a nitrogen atmosphere, cooled, 2ml of water was added and the solids were filtered, washed with EtOH anddried to give 1.23 g (3.30 mmol, 90%) of2-benzothiazol-2-yl-5-(3-bromophenyl)-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 12.90 (bs, 1H), 8.10 (m, 2H), 7.90 (m, 2H), 7.65 (m, 1H),7.50-7.30 (m, 3H), 6.20 (s, 1H).

To a solution of 470 mg (1.26 mmol) of2-benzothiazol-2-yl-5-(3-bromophenyl)-1,2-dihydropyrazol-3-one in 10 mlof THF was added N,N-dimethylformamide dimethylacetal (185 μl, 1.39mmol). The reaction was stirred overnight at room temperature under anitrogen atmosphere. Diethyl ether was added and the solids werefiltered off, washed with diethyl ether and dried to give 487 mg (1.13mmol, 90%) of2-benzothiazol-2-yl-5-(3-bromophenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00 (d, 1H), 7.80 (m, 2H), 7.70 (m, 2H), 7.65 (d,1H), 7.45 (2t, 2H), 7.35 (t, 1H), 3.70 (s, 3H), 3.40 (s, 3H).

A suspension of 467 mg (1.09 mmol) of2-benzothiazol-2-yl-5-(3-bromophenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-onein 10 ml 7N NH3 in MeOH was heated in a pressure vessel to 100° C.overnight. After cooling to room temperature, the solids were filtered,washed with a little EtOH and dried to give 382 mg (0.957 mmol, 88%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(3-bromophenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.60 (bs, 2H), 8.10 (s, 1H), 8.00 (d, 1H), 7.90 (d,1H), 7.80 (s, 1H),7.70 (m, 1H), 7.55 (m, 2H), 7.45 (t, 1H), 7.30 (t,1H).

Example 174-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(3-iodophenyl)-2,4-dihydropyrazol-3-one

A solution of 519 mg (3.14 mmol) of benzothiazol-2-yl-hydrazine and 1.00g (3.14 mmol) of 3-(3-iodophenyl)-3-oxopropionic acid ethyl ester in 20ml of EtOH was refluxed overnight under a nitrogen atmosphere, cooled, 2ml of water was added and the solids were filtered, washed with EtOH anddried to give 1.14 g (2.71 mmol, 86%) of2-benzothiazol-2-yl-5-(3-iodophenyl)-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 13.00 (bs, 1H), 8.25 (s, 1H), 8.05 (d, 1H), 7.90 (m, 2H),7.80 (m, 1H), 7.50 (t, 1H), 7.40 (t, 1H), 7.30 (t, 1H), 6.20 (s, 1H).

To a solution of 393 mg (0.94 mmol) of2-benzothiazol-2-yl-5-(3-iodophenyl)-1,2-dihydropyrazol-3-one in 20 mlof THF was added N,N-dimethylformamide dimethylacetal (137 μl, 1.03mmol). The reaction was stirred for 1 hour at room temperature under anitrogen atmosphere. Diethyl ether was added and the solids werefiltered off, washed with diethyl ether and dried to give 424 mg (0.89mmol, 95%) of2-benzothiazol-2-yl-5-(3-iodophenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00 (m, 2H), 7.90 (d, 1H), 7.80 (d, 1H), 7.70 (s,1H), 7.60 (d, 1H), 7.40 (t, 1H), 7.30 (m, 2H), 3.70 (s, 3H), 3.40 (s,3H).

A suspension of 196 mg (0.413 mmol) of2-benzothiazol-2-yl-5-(3-iodophenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-onein 3 ml 7N NH3 in MeOH was heated to 50° C. for 1.5 hours and left tocool overnight. The solids were filtered, washed with a little EtOH anddried to give 137 mg (0.307 mmol, 74%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(3-iodophenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.50 (bs, 2H), 8.10 (s, 1H), 8.00 (m, 2H), 7.85 (m,2H), 7.80 (d, 1H), 7.45 (t, 1H), 7.30 (m, 2H).

Example 184-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(3-fluorophenyl)-2,4-dihydropyrazol-3-one

A solution of 786 mg (4.76 mmol) of benzothiazol-2-yl-hydrazine and 1.00g (4.76 mmol) of 3-(3-fluorophenyl)-3-oxopropionic acid ethyl ester in25 ml of EtOH was refluxed for 5 hours under a nitrogen atmosphere,cooled and the solids were filtered, washed with EtOH and dried to give870 mg (2.79 mmol, 59%) of2-benzothiazol-2-yl-5-(3-fluorophenyl)-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 13.00 (bs, 1H), 8.10 (d, 1H), 7.90 (d, 1H), 7.75 (m, 2H),7.50 (m, 2H), 7.40 (t, 1H), 7.30 (m, 1H), 6.20 (s, 1H).

To a solution of 480 mg (1.54 mmol) of2-benzothiazol-2-yl-5-(3-fluorophenyl)-1,2-dihydropyrazol-3-one in 10 mlof THF was added N,N-dimethylformamide dimethylacetal (225 μl, 1.70mmol). The reaction was stirred for 3 hours at room temperature under anitrogen atmosphere. Diethyl ether was added and the solids werefiltered off, washed with diethyl ether and dried to give 520 mg (1.42mmol, 92%) of2-benzothiazol-2-yl-5-(3-fluorophenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00 (d, 1H), 7.80 (d, 1H), 7.70 (s, 1H), 7.60 (m,1H), 7.50-7.40 (m, 3H), 7.40-7.30 (m, 2H), 3.70 (s, 3H), 3.40 (s, 3H).

A suspension of 360 mg (0.819 mmol) of2-benzothiazol-2-yl-5-(3-fluorophenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-onein 3 ml 7N NH3 in MeOH was heated in a pressure vessel to 100° C.overnight. After cooling to room temperature the solids were filtered,washed with a little EtOH and dried to give 249 mg (0.736 mmol, 90%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(3-fluorophenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.40 (bs, 2H), 8.10 (s, 1H), 8.00 (d, 1H), 7.85 (d,1H), 7.60 (m, 3H), 7.45 (t, 1H), 7.35 (m, 2H).

Example 194-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(3-t-butylphenyl)-2,4-dihydropyrazol-3-one

To a suspension of 984 mg NaH (24.60 mmol, 60% dispersion in mineraloil) in 15 ml of dry benzene under a nitrogen atmosphere was slowlyadded diethyl carbonate (2.10 ml, 16.40 mmol) and 3-t-butylacetophenone(1.45 g, 8.20 mmol). The reaction mixture was heated to reflux for 30minutes. The mixture was cooled to room temperature, 3 ml of AcOH wasslowly added followed by water and extraction with EtOAc. The organiclayer was dried over magnesium sulfate, evaporated and the residue waspurified by column chromatography (silica, PE (40-60)/EtOAc 20:1) togive 1.45 g (5.84 mmol, 71%) of 3-(3-t-butylphenyl)-3-oxopropionic acidethyl ester.

A solution of 964 mg (5.84 mmol) of benzothiazol-2-yl-hydrazine and 1.45g (5.84 mmol) of 3-(3-t-butylphenyl)-3-oxopropionic acid ethyl ester in5 ml of EtOH and 5 ml of HOAc was refluxed overnight under a nitrogenatmosphere, cooled and the solids were filtered, washed with EtOH anddried to give 1.70 g (4.86 mmol, 83%) of2-benzothiazol-2-yl-5-(3-t-butylphenyl)-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 13.05 (bs, 1H), 8.10 (d, 1H), 7.90 (m, 2H), 7.70 (d, 1H),7.55-7.30 (m, 4H), 6.10 (s, 1H), 1.35 (s, 9H).

To a solution of 1.00 g (2.86 mmol) of2-benzothiazol-2-yl-5-(3-t-butylphenyl)-1,2-dihydropyrazol-3-one in 20ml of THF was added N,N-dimethylformamide dimethylacetal (4.20 μl, 3.15mmol). The reaction was stirred for 3 hours at room temperature under anitrogen atmosphere, the solids were filtered off, washed with diethylether and dried to give 690 mg (1.70 mmol, 60%) of2-benzothiazol-2-yl-5-(3-t-butylphenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00 (d, 1H), 7.80 (d, 1H), 7.65 (s, 1H), 7.60 (s,1H), 7.55 (m, 1H), 7.45 (m, 3H), 7.30 (t, 1H), 3.70 (s, 3H), 3.40 (s,3H), 1.35 (s, 9H).

A suspension of 150 mg (0.371 mmol) of2-benzothiazol-2-yl-5-(3-t-butylphenyl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-onein 5 ml 7N NH3 in MeOH was heated to 60° C. for 2 hours. After coolingto room temperature the solids were filtered, washed with a little EtOHand dried to give 114 mg (0.302 mmol, 82%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(3-t-butylphenyl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.45 (bs, 2H), 8.05 (d, 1H), 7.95 (s, 1H), 7.85 (d,1H), 7.70 (s, 1H), 7.60-7.40 (m, 3H), 7.30 (m, 2H), 1.35 (s, 9H).

Example 204-[1-Aminomethylidene]-2-(6-methoxybenzothiazol-2-yl)-5-phenyl-2,4-dihydropyrazol-3-one

A solution of 1.33 g (6.81 mmol) of(6-methoxybenzothiazol-2-yl)-hydrazine and 1.44 g (7.49 mmol) of ethylbenzoylacetate in 40 ml of EtOH was refluxed overnight under a nitrogenatmosphere. The solids were filtered off, washed with EtOH and dried togive 1.96 g (6.06 mmol, 89%) of2-(6-methoxybenzothiazol-2-yl)-5-phenyl-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 12.85 (bs, 1H), 7.85 (m, 2H), 8.00 (d, 1H), 7.65 (d, 1H),7.45 (m, 2H), 7.10 (d, 1h), 6.10 (s, 1H), 3.80 (s, 3H).

To a solution of 364 mg (1.13 mmol) of2-(6-methoxybenzothiazol-2-yl)-5-phenyl-1,2-dihydropyrazol-3-one in 15ml of THF was added N,N-dimethylformamide dimethylacetal (164 μl, 1.24mmol). The reaction was stirred overnight at room temperature under anitrogen atmosphere, after which, the solids were filtered off, washedwith diethyl ether and dried to give 372 mg (0.983 mmol, 87%) of2-(6-methoxybenzothiazol-2-yl)-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 7.70-7.45 (m, 8H), 7.00 (d, 1H), 3.80 (s, 3H), 3.70(s, 3H), 3.40 (s, 3H).

A suspension of 240 mg (0.634 mmol) of2-(6-methoxybenzothiazol-2-yl)-4-[1-dimethylaminomethylidene]-5-phenyl-2,4-dihydropyrazol-3-onein 10 ml 7N NH3 in MeOH was heated to 100° C. in a pressure vesselovernight. After cooling to room temperature, the solids were filtered,washed with a little EtOH and dried to give 192 mg (0.548 mmol, 86%) of4-[1-aminomethylidene]-2-(6-methoxybenzothiazol-2-yl)-5-phenyl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.45 (bs, 2H), 8.00 (bs, 1H), 7.70 (m, 3H), 7.60 (s,1H), 7.50 (m, 3H), 7.05 (d, 1H), 3.80 (s, 3H).

Example 214-[1-Aminomethylidene]-2-benzothiazol-2-yl-5-(3-bromothiophen-2-yl)-2,4-dihydropyrazol-3-one

To a suspension of 628 mg NaH (15.70 mmol, 60% dispersion in mineraloil) in 25 ml of THF under a nitrogen atmosphere was slowly addeddiethyl carbonate (1.90 ml, 15.70 mmol) and1-(3-bromo-thiophen-2-yl)-ethanone (1.61 g, 7.85 mmol). The reactionmixture was heated to 70° C. for 2 hours, cooled to room temperaturepoured into ice water followed by some AcOH and extracted with 2× EtOAc.The combined organic layers were washed with water 3×, washed withbrine, dried over magnesium sulfate, evaporated and the residue waspurified by column chromatography (silica, 25% EtOAc in PE (40/60) togive 1.54 g (5.84 mmol, 71%) of 3-(3-bromothiophen-2-yl)-3-oxo-propionicacid ethyl ester.

A solution of 918 mg (5.56 mmol) of benzothiazol-2-yl-hydrazine and 1.54g (5.56 mmol) of 3-(3-bromothiophen-2-yl)-3-oxo-propionic acid ethylester in 25 ml of EtOH/AcOH (1:1) was refluxed overnight under anitrogen atmosphere, cooled, the solids were filtered off, washed withEtOH and dried to give 711 mg (1.88 mmol, 34%) of2-benzothiazol-2-yl-5-(3-bromothiophen-2-yl)-1,2-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 13.00 (bs, 1H), 8.10 (d, 1H), 7.90 (d, 1H), 7.70 (s,1H), 7.50 (t, 1H), 7.40 (t, 1H), 7.20 (m, 1h), 6.30 (s, 1H).

To a solution of 700 mg (1.85 mmol) of2-benzothiazol-2-yl-5-(3-bromothiophen-2-yl)-1,2-dihydropyrazol-3-one in7 ml of THF was added N,N-dimethylformamide dimethylacetal (258 μl, 1.94mmol). The reaction was stirred for 1 hour at room temperature under anitrogen atmosphere, after which, the solids were filtered off, washedwith diethyl ether and dried to give 550 mg (1.26 mmol, 69%) of2-benzothiazol-2-yl-5-(3-bromothiophen-2-yl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00 (d, 1H), 7.90 (d, 1H), 7.80 (d, 1H), 7.60 (s,1H), 7.45 (t, 1H), 7.30 (m, 2H), 3.80 (s, 3H), 3.40 (s, 3H).

A suspension of 210 mg (0.485 mmol) of2-benzothiazol-2-yl-5-(3-bromothiophen-2-yl)-4-[1-dimethylaminomethylidene]-2,4-dihydropyrazol-3-onein 5 ml 7N NH3 in MeOH was heated to 60° C. overnight. After cooling toroom temperature, the solids were filtered, washed with a little EtOHand dried to give 198 mg (0.472 mmol, 97%) of4-[1-aminomethylidene]-2-benzothiazol-2-yl-5-(3-bromothiophen-2-yl)-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.25 (bs, 2H), 8.05 (d, 1H), 7.85 (m, 3H), 7.45 (t,1H), 7.30 (m, 2H).

Example 222-Benzothiazol-2-yl-4-[1-methylaminomethylidene]-5-thiophen-2-yl-2,4-dihydropyrazol-3-one

To a suspension of 628 mg NaH (15.70 mmol, 60% dispersion in mineraloil) in 10 ml of THF under a nitrogen atmosphere was slowly addeddiethyl carbonate (1.90 ml, 15.70 mmol) and 2-acetylthiophene (1.00 g,7.92 mmol). The reaction mixture was heated to 70° C. for 1 hour, cooledto room temperature poured into ice water, AcOH was added and thereaction mixture was with extracted twice with diethyl ether. Thecombined organic layers were washed with water, brine, dried overmagnesium sulfate, evaporated and the residue was purified by columnchromatography (silica, DCM) to give 1.27 g (6.41 mmol, 80%) of3-oxo-3-thiophen-2-yl-propionic acid ethyl ester.

A solution of 1.06 g (6.41 mmol) of benzothiazol-2-yl-hydrazine and 1.27g (6.41 mmol) of 3-oxo-3-thiophen-2-yl-propionic acid ethyl ester in 15ml of EtOH was refluxed overnight under a nitrogen atmosphere, cooled,the solids were filtered off, washed with EtOH and dried to give 1.30 g(4.34 mmol, 68%) of2-benzothiazol-2-yl-5-thiophen-2-yl-1,2-dihydropyrazol-3-one. ¹H-NMR(DMSO-d6): δ 13.00 (bs, 1H), 8.05 (d, 1H), 7.90 (d, 1H), 7.70 (m, 2H),7.50 (t, 1H), 7.40 (t, 1H), 7.20 (s, 1h), 6.00 (s, 1H).

To a solution of 137 mg (0.458 mmol) of2-benzothiazol-2-yl-5-thiophen-2-yl-1,2-dihydropyrazol-3-one in 6 ml ofTHF was added N,N-dimethylformamide dimethylacetal (64 μl, 0.480 mmol).The reaction was stirred for 10 minutes at room temperature under anitrogen atmosphere, after which, the solids were filtered off, washedwith diethyl ether and dried to give 162 mg (0.458 mmol, 100%) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-thiophen-2-yl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 8.00 (m, 2H), 7.85 (d, 1H), 7.75 (d, 1H), 7.55 (m,1H), 7.45 (t, 1H), 7.30 (t, 1H), 7.20 (m, 1H), 3.80 (s, 3H), 3.45 (s,3H).

A suspension of 162 mg (0.458 mmol) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-thiophen-2-yl-2,4-dihydropyrazol-3-onein 5 ml of 33% MeNH2 in EtOH was stirred at room temperature for 1.5hours, the solids were filtered, washed with EtOH and dried to give 47mg (0.138 mmol, 30%) of2-benzothiazol-2-yl-4-[1-methylaminomethylidene]-5-thiophen-2-yl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 9.95 (bs, 1H), 8.20 (s, 1H), 8.00 (d, 1H), 7.85 (d,1H), 7.75 (m, 2H), 7.45 (t, 1H), 7.35 (t, 1H), 7.20 (s, 1H), 3.30 (s,3H).

Example 232-Benzothiazol-2-yl-5-methyl-4-[1-piperidin-1-ylmethylidene]-2,4-dihydropyrazol-3-one

A solution of 2.00 g (12.10 mmol) of benzothiazol-2-ylhydrazine and 1.62ml (12.71 mmol) of ethyl acetoacetate in 40 ml of acetic acid wasrefluxed under a nitrogen atmosphere for 2.5 hours and stirred at roomtemperature overnight. 50 ml of water was added and the precipitate wascollected by filtration, washed with water and dried to give 2.68 g(11.59 mmol, 96%) of2-benzothiazol-2-yl-5-methyl-1,2-dihydropyrazol-3-one. ¹H-NMR (DMSO-d6):δ 12.80 (bs, 1H), 8.00 (d, 1H), 7.80 (d, 1H), 7.50 (t, 1H), 7.35 (t,1H), 5.25 (s, 1H), 2.20 (s, 3H).

To a suspension of 220 mg (0.951 mmol) of2-benzothiazol-2-yl-5-methyl-1,2-dihydropyrazol-3-one in 20 ml toluenewas added N,N-dimethylformamide dimethylacetal (135 μl, 1.00 mmol). Thereaction was stirred for 4 hours at room temperature under a nitrogenatmosphere, after which time, the solvent was evaporated and theremaining solids were washed with diethyl ether and dried to give 180 mg(0.629 mmol, 66%) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-methyl-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 7.95 (d, 1H), 7.75 (d, 1H), 7.65 (s, 1H), 7.40 (t,1H), 7.25 (t, 1H), 3.75 (s, 3H), 3.40 (s, 3H), 2.20 (s, 3H).

To a suspension of 1.80 g (6.29 mmol) of2-benzothiazol-2-yl-4-[1-dimethylaminomethylidene]-5-methyl-2,4-dihydropyrazol-3-onein a mixture of 15 ml of toluene and 10 ml of DMF was added 5 ml of a 4NNaOH solution. The reaction mixture was stirred under a nitrogenatmosphere at room temperature for 4 hours, after which time, the solidswere filtered off and dried in vacuo to give2-benzothiazol-2-yl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carbaldehyde(6.29 mmol; 100%). ¹H-NMR (DMSO-d6): δ 9.30 (s, 1H), 8.45 (s, 1H), 7.90(d, 1H), 7.70 (d, 1H), 7.40 (t, 1H), 7.20 (t, 1H), 2.20 (2, 3H).

A mixture of 160 mg (0.617 mmol) of2-benzothiazol-2-yl-5-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carbaldehyde,piperidine (720 μl, 7.35 mmol) and 2 drops of concentrated HCl wasrefluxed overnight under a nitrogen atmosphere, cooled, evaporated todryness and the residue purified by column chromatography (silica, 4%methanol in dichloromethane) to give 100 mg (0.306 mmol, 50%) of2-benzothiazol-2-yl-5-methyl-4-[1-piperidin-1-yl-methylidene]-2,4-dihydropyrazol-3-one.¹H-NMR (DMSO-d6): δ 7.95 (d, 1H), 7.75 (d, 1H), 7.65 (s, 1H), 7.40 (t,1H), 7.25 (t, 1H), 4.50 (bs, 2H), 3.75 (bs, 2H), 2.00 (s, 3H), 1.70 (bs,4H), 1.65 (bs, 2H).

Example 24 Biological Methods

The PC-3 prostate cancer cell line (ATCC# CRL-1435) was maintained inRPMI-1640 medium (Invitrogen, 31870), supplemented with 10% Fetal BovineSerum (Sigma, F7524), L-Glutamine (Invitrogen 25030-024). Cells weresplit once a week at a 1:10 ratio.

Example 25 Cell Invasion Assay

For cell invasion assays, PC3 cells were incubated in the presence of acompound according to the invention (10 μM) for 4 days, prior to theinvasion assay. Forty thousand cells were seeded into BD BiocoatMatrigel Invasion chambers (8 micron; BD 354480) in serum-free medium.The invasion chamber was placed in a 24-well containing medium with 10%fetal calf serum as chemo-attractant. As a control, the same amount ofcells was seeded in 24-well culture plates. After 48 hours incubation,cells in the invasion chamber were removed by aspiration and cleaningthe inner compartment with a cotton swab. The invasion chamber was thenput into CellTiter-GLO (CTG, Promega-G7571) cell viability reagent,incubated for 15 minutes, and then analyzed on a Victor3 luminometer.Cell invasion was calculated as the CTG activity on the lower part ofthe membrane divided by the CTG activity of the cells grown in a 24 wellplate. Inhibition of cell invasion by a specific compound was estimatedby comparing the amount of cell invasion of compound-treated cellsversus DMSO treated cells.

1. A method for the treatment of carcinoma, the method comprising:administering to a subject suffering from carcinoma a compound havingthe structure according to formula III:

wherein: X is NH or S; R¹ is H or (1C-4C)alkyl; R² is (1C-4C)alkyl,phenyl or a monocyclic aromatic ring having one or more N—, O— or S—atoms in the ring; R³ and R⁴ are each independently H, (1C-6C)alkyl,(2C-6C) alkenyl, (2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl, phenyl, amonocyclic aromatic ring having one or more N—, O— or S— atoms in thering, a monocyclic non-aromatic ring having one or more N—, O— or S—atoms in the ring; or R³ and R⁴ form together a pyrrolyl, imidazolyl,pyrazolyl, pyrrolidinyl, pyrrolinylimidazolidinyl, imidazolinyl,piperidyl, or piperazinylmorpholinyl; R⁵ is H, Cl, F, Br, Me, NO₂,t-butyl, OCF₃, OCH₃, or CF₃; R⁶ is H, (1C-4C)alkyl, (1C-4C)alkyloxy,halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, nitro or halogen; R⁷ is H, F, Cl,Br, Me, NO₂, t-butyl, OCF₃, OCH₃, or CF₃; or a pharmaceuticallyacceptable addition salt thereof.
 2. The method according to claim 1,wherein R³ and R⁴ each independently represent hydrogen, methyl, ethylor propyl or a group as selected from list of structures consisting of:

or R³ and R⁴ form together a substituted ring as represented in thefollowing structures:


3. The method according to claim 1, wherein: R¹ is H or (1C-4C)alkyl; R²is (1C-4C)alkyl, phenyl or a monocyclic aromatic ring having one or moreN—, O— or S— atoms in the ring; R⁵ and R⁶ are hydrogen; R⁷ is H.
 4. Themethod according to claim 1, wherein X is S.
 5. The method according toclaim 1, wherein R¹ is H or (1C-4C)alkyl and R² is (1C-4C)alkyl orphenyl.
 6. The method according to claim 1, wherein R³ is hydrogen. 7.The method according to claim 1, wherein R³ and R⁴ represent both methylor R³ is hydrogen.
 8. A compound having a structure according to formulaII:

or a pharmaceutically acceptable addition salt thereof.
 9. A compoundaccording to formula I:

wherein: X is NH or S; R¹ is H or (1C-4C)alkyl; R² is —Z or —Y—Z,wherein Y is —CH₂— or —CH₂—CH₂— and or Z is thien 2 yl or Z isN-methylpyrol-3-yl or benzo[b]thien-2-yl or 2-naphthalenyl; R³ and R⁴are each independently H, (1C-6C)alkyl, (2C-6C) alkenyl, (2C-6C)alkynyl,cyano, (3C-6C)cycloalkyl, a monocyclic aromatic ring having one or moreN—, O— or S— atoms in the ring, a monocyclic non-aromatic ring havingone or more N—, O— or S— atoms in the ring; or R³ and R⁴ form together apyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl, pyrrolinylimidazolidinyl,imidazolinyl, piperidyl, piperazinylmorpholinyl; R⁵ is H or CF₃; R⁶ isH, (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl, halo(1C-4C)alkyloxy,nitro or halogen; or a pharmaceutically acceptable addition saltthereof.
 10. A compound according to formula I:

wherein: X is NH or S; R¹ is H or (1C-4C)alkyl; R² is a monocyclicaromatic ring having one or more N—, O— or S— atoms in the ring; R³ andR⁴ are each independently H, (1C-6C)alkyl, (2C-6C) alkenyl,(2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl, a monocyclic non-aromatic ringhaving one or more N—, O— or S— atoms in the ring; or R³ and R⁴ formtogether pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl,pyrrolinylimidazolidinyl, imidazolinyl, piperidyl,piperazinylmorpholinyl; R⁵ is H or CF₃; R⁶ is H, (1C-4C)alkyl,(1C-4C)alkyloxy, halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, nitro orhalogen; or a pharmaceutically acceptable addition salt thereof.
 11. Thecompound of claim 9, wherein: X is S; R¹ is H; R² is Z and Z is phenyl;or Z is thien 2 yl; or Z is N-methylpyrol-3-yl or benzo[b]thien-2-yl or2-naphthalenyl; R³, R⁴ are H, H or H, CH₃ or CH₃, CH₃; R⁵ is H; R⁶ is H,halogen or methoxy; or a pharmaceutically acceptable addition saltthereof.
 12. The compound of claim 9, wherein R⁶ is methoxy.
 13. Acompound according to Formula III:

wherein: X is S; R¹ is H, or CH₃; R² is CF₃, CH₃, phenylethyl,

wherein R^(a) is H, F, Cl, Br, I, NO₂, methyl, ethyl, isopropyl,t-butyl, methoxy or CF₃ and R^(b) is H, Cl or CH₃; R³, R⁴ is H, H or H,CH₃, or CH₃, CH₃ or one of R³ or R⁴ is —CN or D-methoxyphenylmethyl orR³ and R⁴ together represent a ring

on the nitrogen of Formula III to represent a piperidyl or R³ and R⁴together represent a ring

on the nitrogen of Formula III to pyrrolidinyl, or R³ is methyl and R⁴is dichlorbenzyl

R⁵ is H, Cl, F, Br, Me, NO₂, t-butyl, OCF₃, OCH₃, or CF₃, R⁶ is H, F,Cl, Br, NO₂, CH₃, t-butyl, OCH₃, OCF₃, or CF₃; R7 is H, F, Cl, Br, Me,NO2, t-butyl, OCF3, OCH3, or CF3, or a pharmaceutically acceptableaddition salt thereof.
 14. The compound of claim 13, wherein: R² is CF₃,CH₃, phenylethyl,

wherein R^(a) is H, F, Cl, Br, I, NO₂, methyl, ethyl, isopropyl,t-butyl, methoxy or CF₃ and R^(b) is H, Cl or CH₃; R³, R⁴ is H, H or H,CH₃, or CH₃, CH₃ or one of R³ or R⁴ is —CN or n-methoxyphenylmethyl orR³ and R⁴ together represent a ring

on the nitrogen of Formula III to represent a piperidyl or R³ and R⁴together represent a ring

on the nitrogen of Formula III to pyrrolidinyl, or R³ is methyl and R⁴is dichlorbenzyl

R⁵ is H, or Cl; R⁶ is H, F, Cl, NO₂, CH₃, t-butyl, OCH₃ or OCF₃; R⁷ isH, or Cl; or a pharmaceutically acceptable addition salt thereof. 15.The compound of claim 13, wherein: R¹ is H; R² is CF₃, CH₃, phenylethyl,

wherein R^(a) is H, F, Cl, Br, I, NO₂, methyl, ethyl, isopropyl,t-butyl, methoxy or CF₃ and R^(b) is H, Cl or CH₃; R³, R⁴ is H, H or H,CH₃, or together represent a ring

on the nitrogen of Formula III to represent piperidyl, or R³ is methyland R⁴ is dichlorbenzyl

R⁵ is H; R⁶ is H, Cl, NO₂, CH₃, OCH₃, OCF₃; R⁷ is H.
 16. The compoundclaim 13, wherein: R¹ is H; R² is CF₃, CH₃,

wherein R^(a) is H, F, Cl, Br, I, methyl, ethyl, isopropyl, t-butyl orCF₃ and R^(b) is H, Cl or CH₃; R³, R⁴ is H, H or H, CH₃, or togetherrepresent a ring

on the nitrogen of Formula III to represent piperidyl, or R³ is methyland R⁴ is dichlorbenzyl

R⁵ is H; R⁶ is H, Cl, NO₂, CH₃, OCH₃, OCF₃; R⁷ is H; or apharmaceutically acceptable addition salt thereof.
 17. A method for thetreatment or prevention of cancer, the method comprising administeringthe compound of claim 9 to a subject suffering from cancer.
 18. Themethod according to claim 17, wherein the cancer is a carcinoma.
 19. Themethod according to claim 18, wherein the carcinoma is selected from thegroup consisting of gastric cancer, bladder cancer, esophageal cancer,breast cancer, prostate cancer and pancreas cancer.
 20. The methodaccording to claim 19 wherein the carcinoma is prostate cancer.
 21. Themethod according to claim 17, wherein the method of treatment results indelaying, preventing, treating or reversing metastasis.
 22. Apharmaceutical composition comprising the compound of claim
 9. 23. Thepharmaceutical composition claim 22, further comprising one or moreadditional compounds with therapeutic effects in treatment of acarcinoma.
 24. The method according to claim 1, wherein the alkyl,phenyl or aromatic ring of R² is substituted with one or more groupsselected from the group consisting of (1C-4C)alkyl, (1C-4C)alkyloxy,halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, phenyloxy, phenylthio, halogen,and nitro.
 25. The method according to claim 1, wherein R³ is a(1C-6C)alkyl, (2C-6C) alkenyl, (2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl,phenyl, a monocyclic aromatic ring having one or more N—, O— or S— atomsin the ring, a monocyclic non-aromatic ring having one or more N—, O— orS— atoms in the ring and wherein R³ is substituted with a hydroxyl,(1C-4C)alkoxy, phenyl, cycloalkyl, piperidyl, piperazinyl, furyl,thienyl, pirazinyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl, isoxazolyl,isothiazolyl, pyrrolidonyl, pyrrolinyl, imidazolinyl, imidazolyl, ormonocyclic aromatic ring having one or more N—, O— or S— atoms in thering.
 26. The method according to claim 25, wherein the substitutionhydroxyl, (1C-4C)alkoxy, phenyl, cycloalkyl, piperidyl, piperazinyl,furyl, thienyl, pirazinyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl, isoxazolyl,isothiazolyl, pyrrolidonyl, pyrrolinyl, imidazolinyl, imidazolyl, ormonocyclic aromatic ring having one or more N—, O— or S— atoms in thering is further substituted with (1C-4C)alkyl, (1C-4C)alkyloxy,halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, halogen, nitro or (1C-2C)dioxolforming a ring;
 27. The method according to claim 1, wherein R⁴ is a(1C-6C)alkyl, (2C-6C) alkenyl, (2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl,phenyl, a monocyclic aromatic ring having one or more N—, O— or S— atomsin the ring, a monocyclic non-aromatic ring having one or more N—, O— orS— atoms in the ring and wherein R⁴ is substituted with a hydroxyl,(1C-4C)alkoxy, phenyl, cycloalkyl, piperidyl, piperazinyl, furyl,thienyl, pirazinyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl, isoxazolyl,isothiazolyl, pyrrolidonyl, pyrrolinyl, imidazolinyl, imidazolyl, ormonocyclic aromatic ring having one or more N—, O— or S— atoms in thering.
 28. The method according to claim 27, wherein the substitutionhydroxyl, (1C-4C)alkoxy, phenyl, cycloalkyl, piperidyl, piperazinyl,furyl, thienyl, pirazinyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl, isoxazolyl,isothiazolyl, pyrrolidonyl, pyrrolinyl, imidazolinyl, imidazolyl, ormonocyclic aromatic ring having one or more N—, O— or S— atoms in thering is further substituted with (1C-4C)alkyl, (1C-4C)alkyloxy,halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, halogen, nitro or (1C-2C)dioxolforming a ring;
 29. The method according to claim 1, wherein R³ and R⁴form together a pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl,pyrrolinylimidazolidinyl, imidazolinyl, piperidyl, orpiperazinylmorpholinyl, wherein each of the foregoing is substitutedwith (1C-6C)alkyl, phenyl(1C-4C)alkyl, or phenylketo(1C-4C)alkyl. 30.The method according to claim 3, wherein alkyl, phenyl or aromatic ringof R² is substituted with one or more groups selected from the groupconsisting of a (1C-4C)alkyl and a halogen.
 31. The compound of claim 9,wherein Z is phenyl or a monocyclic aromatic ring having one or more N—,O— or S— atoms in the ring, and wherein Z is substituted with one ormore groups selected from the group consisting of (1C-4C)alkyl,(1C-4C)alkyloxy, halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, phenyloxy,phenylthio, halogen, or nitro from (1C-4C)alkyl, (1C-4C)alkyloxy,halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, phenyloxy, phenylthio, halogen,and nitro.
 32. The compound of claim 9, wherein Z is thien-2-ylsubstituted at position 3, 4 or 5 with a halogen.
 33. The compound ofclaim 9, wherein R³ is (1C-6C)alkyl, (2C-6C) alkenyl, (2C-6C)alkynyl,cyano, (3C-6C)cycloalkyl, a monocyclic aromatic ring having one or moreN—, O— or S— atoms in the ring, a monocyclic non-aromatic ring havingone or more N , O— or S— atoms in the ring and wherein R³ is substitutedwith a hydroxyl, (1C-4C)alkoxy, cycloalkyl, piperidyl, piperazinyl,furyl, thienyl, pirazinyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl, isoxazolyl,isothiazolyl, pyrrolidonyl, pyrrolinyl, imidazolinyl, imidazolyl, or amonocyclic aromatic ring having one or more N—, O— or S— atoms in thering.
 34. The compound of claim 33, wherein the substitution hydroxyl,(1C-4C)alkoxy, cycloalkyl, piperidyl, piperazinyl, furyl, thienyl,pirazinyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl,pyrrolidonyl, pyrrolinyl, imidazolinyl, imidazolyl, a monocyclicaromatic ring having one or more N—, O— or S— atoms in the ring isfurther substituted with (1C-4C)alkyl, (1C-4C)alkyloxy,halo(1C-4C)alkyl, halo(1C-4C)alkyloxy, halogen, nitro or (1C-2C)dioxolforming a ring;
 35. The compound of claim 9, wherein R⁴ is (1C-6C)alkyl,(2C-6C) alkenyl, (2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl, a monocyclicaromatic ring having one or more N—, O— or S—30 atoms in the ring, amonocyclic non-aromatic ring having one or more N—, O— or S— atoms inthe ring and wherein R⁴ is substituted with a hydroxyl, (1C-4C)alkoxy,cycloalkyl, piperidyl, piperazinyl, furyl, thienyl, pirazinyl, pyrrolyl,2H-pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrrolidonyl,pyrrolinyl, imidazolinyl, imidazolyl, or a monocyclic aromatic ringhaving one or more N—, O— or S— atoms in the ring.
 36. The compound ofclaim 35, wherein the substitution hydroxyl, (1C-4C)alkoxy, cycloalkyl,piperidyl, piperazinyl, furyl, thienyl, pirazinyl, pyrrolyl,2H-pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrrolidonyl,pyrrolinyl, imidazolinyl, imidazolyl, a monocyclic aromatic ring havingone or more N—, O— or S— atoms in the ring is further substituted with(1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl, halo(1C-4C)alkyloxy,halogen, nitro or (1C-2C)dioxol forming a ring.
 37. The compound ofclaim 9, wherein R³ and R⁴ form together a pyrrolyl, imidazolyl,pyrazolyl, pyrrolidinyl, pyrrolinylimidazolidinyl, imidazolinyl,piperidyl, or piperazinylmorpholinyl, wherein each of the foregoing issubstituted with (1C-6C)alkyl, phenyl(1C-4C)alkyl, orphenylketo(1C-4C)alkyl.
 38. The compound of claim 10, wherein thearomatic ring of R² is substituted with one or more groups selected fromthe group consisting of (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,halo(1C-4C)alkyloxy, phenyloxy, phenylthio, halogen, and nitro.
 39. Thecompound of claim 10, wherein R³ is a (1C-6C)alkyl, (2C-6C) alkenyl,(2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl, a monocyclic non-aromatic ringhaving one or more N—, O— or S— atoms in the ring and wherein R³ issubstituted with a hydroxyl, (1C-4C)alkoxy, cycloalkyl, piperidyl,piperazinyl, furyl, thienyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyrrolidonyl, pyrrolinyl, imidazolinyl, orimidazolyl.
 40. The compound of claim 39, wherein the substitutionhydroxyl, (1C-4C)alkoxy, cycloalkyl, piperidyl, piperazinyl, furyl,thienyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl,pyrrolidonyl, pyrrolinyl, imidazolinyl, imidazolyl is furthersubstituted with (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,halo(1C-4C)alkyloxy, halogen, nitro or (1C-2C)dioxol forming a ring. 41.The compound of claim 10, wherein R⁴ is a (1C-6C)alkyl, (2C-6C) alkenyl,(2C-6C)alkynyl, cyano, (3C-6C)cycloalkyl, a monocyclic non-aromatic ringhaving one or more N—, O— or S— atoms in the ring and wherein R⁴ issubstituted with a hydroxyl, (1C-4C)alkoxy, cycloalkyl, piperidyl,piperazinyl, furyl, thienyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyrrolidonyl, pyrrolinyl, imidazolinyl, orimidazolyl.
 42. The compound of claim 41, wherein the substitutionhydroxyl, (1C-4C)alkoxy, cycloalkyl, piperidyl, piperazinyl, furyl,thienyl, pyrrolyl, 2H-pyrrolyl, pyrazolyl, isoxazolyl, isothiazolyl,pyrrolidonyl, pyrrolinyl, imidazolinyl, imidazolyl is furthersubstituted with (1C-4C)alkyl, (1C-4C)alkyloxy, halo(1C-4C)alkyl,halo(1C-4C)alkyloxy, halogen, nitro or (1C-2C)dioxol forming a ring. 43.The compound of claim 10, wherein R³ and R⁴ form together a pyrrolyl,imidazolyl, pyrazolyl, pyrrolidinyl, pyrrolinylimidazolidinyl,imidazolinyl, piperidyl, piperazinylmorpholinyl, wherein each of theforegoing is substituted with (1C-6C)alkyl, phenyl(1C-4C)alkyl, orphenylketo(1C-4C)alkyl.
 44. The compound of claim 11, wherein is phenyland is substituted at meta or para position, or at both positions, withone or two substituents selected from the group consisting of —NO₂,halogen, CF₃, (1C-4C)alkyl and methoxy.
 45. The compound of claim 11,wherein Z is thien-2-yl, and is substituted at least one of positions 3,4 and 5 with halogen.